CN106164063A

CN106164063A - There is the hydrophilic polymer derivant of ring-type benzylidene acetal linking group

Info

Publication number: CN106164063A
Application number: CN201580018321.7A
Authority: CN
Inventors: 粒崎拓真; 山本裕二
Original assignee: NOF Corp
Current assignee: NOF Corp
Priority date: 2014-03-31
Filing date: 2015-03-30
Publication date: 2016-11-23
Anticipated expiration: 2035-03-30
Also published as: EP3130587A4; JP6631827B2; US20170107325A1; EP3130587B1; US11530295B2; JP2016065202A; US20200291178A1; WO2015152182A1; CN106164063B; EP3130587A1

Abstract

Provide a kind of hydrophilic polymer derivant, this hydrophilic polymer derivant has the acetal linking group of the hydrolysis rate under the pH that can accurately control its weak acid environment in life entity, and it does not discharge the low molecular weight substance beyond the medicine etc. of hydrophilic polymer chain or connection, more specifically low-molecular-weight aldehydes when hydrolysis.The present invention relates to a kind of hydrophilic polymer derivant, this hydrophilic polymer derivant has ring-type benzylidene acetal linking group, following formula (1) represent:Wherein, R¹And R⁶It is hydrogen atom or alkyl independently of one another；R²、R³、R⁴And R⁵Be independently of one another electrophilic or give electron substituent group or hydrogen atom；X¹It it is chemical reactivity functional group；P is hydrophilic polymer；S is 1 or 2, and t is 0 or 1, and s+t is 1 or 2；W is the integer of 1 to 8；And Z¹And Z²It it is the divalent spacer thing being each independently selected.

Description

There is the hydrophilic polymer derivant of ring-type benzylidene acetal linking group

Technical field

The present invention relates to a kind of hydrophilic polymer derivant, this hydrophilic polymer derivant has can be acid-hydrolyzed Acetal linking group, and for the chemical modification of biological functionality molecule, described biological functionality molecule such as has physiology to live Protein, peptide, antibody, nucleic acid or the low-molecular-weight drug of property and the pharmaceutical carrier of such as liposome and polymer micelle.

Background technology

In drug delivery system, use the hydrophilic polymer with low antigenicity to biological functionality molecule or medicine The chemical modification of carrier is to improve water solubility and the bioavailability of these medicines etc. and extend the circulation time in blood Effective technology.On the other hand, it is known that the medicine etc. being incorporated into hydrophilic polymer be transported to by for target tissue or Behind site, hydrophilic polymer the hydration layer formed reduces the interaction with cell membrane, and suppresses such as to intracellular Absorption and endosome effusion internal/intracellular kinetics.For this problem, have been carried out a kind of by when suitable Between hydrophilic polymer chain is overcome problem from the desorption such as medicine method.Most of strategies make use of life entity various piece Environmental change, such as, reproducibility environment or the existence of certain enzyme or disappearance, as hydrophilic polymer chain desorption touch Send out, and one of them is the technology utilizing pH to change.

Known compared with normal structure, in life entity, the periphery of tumor tissues is sour environment, and medicine etc. is logical Cross endocytosis passage introduce intracellular after, the pH within endosome is gradually lowered.Therefore, take off for selectivity under sour environment The purpose of attached hydrophilic polymer is it has been reported that substantial amounts of have the sour hydrolyzable acetal linking group that introduces in its structure The synthesis example of hydrophilic polymer derivant.But, wherein can control the water-disintegrable example of acetal linking group, And many examples have problems in the method introducing acetal linking group.

Such as, patent document 1 discloses that a kind of branched polyethylene glycol derivant and synthetic method thereof, wherein as having Two polyglycol chains of the water-soluble polymer of low antigenicity are connected by the acetal radical derived from various aldehydes or ketones, but also Water-disintegrable any assessment data are not described.And, the synthetic method described in literary composition be by by the Polyethylene Glycol of excess with each Plant aldehydes or ketones reaction, with the method obtaining the polyethyleneglycol derivative with acetal linking group, thus residual after the reaction A large amount of unreacted Polyethylene Glycol.In the case of using mixture to carry out polymer ends activation as raw material, define The impurity as by-product that the end of the most unreacted Polyethylene Glycol is also activated.When the activation by comprising such impurity Polyethylene Glycol when drug modified, result defines with not comprising the poly ethyldiol modified medicine of acetal linking group, Thus the biggest impact produced on the In vivo kinetics and physical property of medicine.Accordingly, it would be desirable to drug reaction before remove Polyethylene Glycol impurity, but in the case of industrial scale production, from the viewpoint of technology and cost, there is polymeric impurities Separation and removal cause the probability of serious ill effect.

The another kind of method obtaining acetal compound is method alcohol and vinyl ethers reacted in acid condition.Example As, in non-patent literature 1, by the vinyl ethers with various functional group is reacted with Polyethylene Glycol, synthesized have logical Cross the polyethyleneglycol derivative of the various functional groups that ethylene acetal linking group connects.But, in this document, the most do not give Go out water-disintegrable assessment data.

In the synthetic method described in non-patent literature 1, owing to the vinyl ethers as low molecular weight compound is compared It is excessively used in Polyethylene Glycol, so not remaining substantial amounts of unreacted Polyethylene Glycol.But, introduced by this synthetic method Acetal radical comprise ethylene acetal structure, therefore, it is possible to the type of acetal radical introduced is restricted.Introducing benzylidene In the case of acetal radical, inevitably form ketal structure, and due to ketal structure acid labile, in synthetic method, The dimerization as by-product that two of which polyglycol chain is connected is formed by ketal group by acidic condition reaction is a large amount of Body impurity.Therefore, the synthetic method described in non-patent literature 1 is dfficult to apply to have the poly-of benzylidene acetal linking group The synthesis of ethylene glycol derivative.

On the other hand, in non-patent literature 2, by synthesis have by use low-molecular-weight model drug hydroxyl and The unit of the acetal radical formed and the polyethyleneglycol derivative of separately synthesized activation and this unit being condensed, has synthesized wherein The several types polyethyleneglycol derivative that low-molecular-weight model drug is connected by aliphatic or benzylidene acetal linking group. In this case, although it is shown that the structural difference influences hydrolysis rate of acetal radical periphery, the i.e. desorption of polyglycol chain Speed, but do not illustrate the dependency of the structure of this speed and acetal radical periphery, and therefore must not believe that and can control water Xie Xing.Similarly, owing to the method is the method using the hydroxyl of low-molecular-weight model drug to form acetal radical, so being difficult to Material in addition to low-molecular-weight drug, the chemical modification of such as protein and pharmaceutical carrier etc. use the method.

As it has been described above, despite for being desorbed the purpose of hydrophilic polymer chain, each under the sour environment in life entity From many examples of the hydrophilic polymer derivant with the acetal linking group introduced in structure, but not about can Desorption rate hydrophilic of the wherein hydrolysis rate of acetal linking group, i.e. hydrophilic polymer chain is accurately controlled under any pH The example of property polymer derivant.

Prior art literature

Patent documentation

Patent documentation 1:WO2005/108463

Non-patent literature

Non-patent literature 1: polymer science the 57th annual meeting of meeting, Japan, Preprints of The Society Of Polymer Science, Japan, 57,1897 (in Mays, 2008)

Non-patent literature 2:Bioconjugate Chem.2004,15,1254-1263

Summary of the invention

The problem that the present invention is to be solved

In the various piece of life entity, the deviation of pH is the least, although and the periphery of such as tumor tissues and normal group In knitting, the pH of 7.4 compares is sour environment, and its pH is faintly acid, about 6.0.Similarly, demonstrate inside endosome 5.5 to The pH of 6.0 and be little by little acidifying and close to lysosomal pH inside faintly acid, and endosome, i.e. 4.5 to 5.0 pH.Owing to endosome is final and lysosome fusion, it is desirable that, in order to avoid it is degraded by lysosomal enzyme, take in endosome Medicine etc. should escape from endosome at the pH of about 5.5.Therefore, being intended to by using in the periphery of such as tumor tissues or A shade of difference in the pH of the various piece of the life entity within endosome and be desorbed hydrophilic polymer chain and control such as position The cellular uptake of point selection and medicine etc. endosome effusion internal/intracellular dynamic (dynamical) in the case of, need to control exactly Make under the pH of the weak acid environment in life entity, the hydrolysis rate of acetal linking group.

It is an object of the invention to provide a kind of hydrophilic polymer derivant, this hydrophilic polymer derivant has can The accurately acetal linking group of the hydrolysis rate under the pH of its weak acid environment in life entity of control, and it is when hydrolysis Low molecular weight substance beyond medicine not discharging hydrophilic polymer chain or connection etc., more specifically low-molecular-weight aldehydes.

The means of solution problem

Having carried out numerous studies to solve the problems referred to above, as result, the present inventor develops a kind of hydrophilic and gathers Compound derivant, this hydrophilic polymer derivant has under the pH that can accurately control its weak acid environment in life entity The ring-type benzylidene acetal linking group of hydrolysis rate, and it does not discharge hydrophilic polymer chain or company when hydrolysis Low molecular weight substance beyond the medicine connect etc., more specifically low-molecular-weight aromatic aldehydes.

It is a feature of the present invention that chemical reactivity functional group and hydrophilic polymer are by having the ring-type benzene of substituent group Methylene acetal linking group connects.By properly selecting the benzene ring substituents of ring-type benzylidene acetal linking group Type and position, it is possible to regulation affects the electron density of acetal radical periphery of the hydrolysis rate of acetal linking group and sterically hindered Degree.Based on this feature, can give acetal linking group preferable hydrolysis rate, and such that it is able to will with arbitrary velocity Hydrophilic polymer chain is desorbed from the medicine etc. being connected to hydrophilic polymer derivant.

It is a further feature of the invention that the phenyl ring of hydrophilic polymer and ring-type benzylidene acetal linking group leads to Cross in life entity stable bonded.Based on this feature, the present invention has this advantage, i.e. when hydrolysis it can be avoided that discharge Low molecular weight substance beyond medicine going out hydrophilic polymer chain or connection etc., more specifically low-molecular-weight aromatic aldehydes.

The hydrophilic polymer derivant of the present invention can have the ring-type benzene methylene of substituent group by performing wherein introducing Coupling reaction between linking group compound and the hydrophilic polymer intermediate of base acetal radical and synthesize.Therefore, there is no need to As in patent documentation 1, the hydrophilic polymer of use excess is to form acetal radical, and need not remove unreacted parent Waterborne polymeric impurity, thus easily produce on an industrial scale.It addition, the type of the acetal radical that can introduce is not limited System, and the benzylidene acetal radical that can not be introduced can be introduced by the synthetic method of non-patent literature 1.Additionally, be different from Non-patent literature 2, in the hydrophilic polymer derivant of the present invention, owing to introducing various at acetal linking group end Functional group, it is possible that form covalent bond with various biological functionality molecules and pharmaceutical carrier.

That is, the present invention includes the following.

[1] a kind of hydrophilic polymer derivant, this hydrophilic polymer derivant has ring-type benzylidene acetal even Connect group, following formula (1) represent:

Wherein R¹And R⁶It is hydrogen atom or alkyl independently of one another；R²、R³、R⁴And R⁵Be independently of one another electrophilic or give electricity Sub-substituent group or hydrogen atom；X¹It it is chemical reactivity functional group；P is hydrophilic polymer；S is 1 or 2, and t is 0 or 1, and s+t It is 1 or 2；W is the integer of 1 to 8；And Z¹And Z²It it is the divalent spacer thing being each independently selected.

[2] the hydrophilic polymer derivant of [1], wherein s is 1 and t to be 0, R²And R⁵It is hydrogen atom independently of one another, And R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-0.30≤Σ σ≤1.05.

[3] the hydrophilic polymer derivant of [1], wherein s is 1 and t to be 0, R²And R⁵In at least one be above-mentioned taking Dai Ji, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-1.71≤Σ σ≤0.88.

[4] the hydrophilic polymer derivant of [1], wherein s is 1 and t to be 1, or s is 2 and t to be 0, R²And R⁵Respectively From being hydrogen atom independently, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-0.19≤Σ σ≤ 0.57。

[5] the hydrophilic polymer derivant of [1], wherein s is 1 and t to be 1, or s is 2 and t to be 0, R²And R⁵In At least one be above-mentioned substituent group, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-0.98≤Σ σ ≤0.48。

[6] the hydrophilic polymer derivant of [1] to [5] any one, wherein X¹Select free active ester groups, active carbonic acid Ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulphur Acyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen amino, acyl The group that diazanyl and azido are formed.

[7] the hydrophilic polymer derivant of [1] to [6] any one, wherein X¹Select free style (a), formula (b), formula C (), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n) are formed Group:

Wherein R⁷It is hydrogen atom or sulfo group；R⁸And R¹¹It is hydrogen atom or the hydrocarbon with 1 to 5 carbon atom independently of one another Base；R⁹Being the alkyl with 1 to 10 carbon atom, this alkyl can comprise halogen atom；And R¹⁰It is former selected from chlorine atom, bromine Son and the halogen atom of atomic iodine.

[8] the hydrophilic polymer derivant of [1] to [7] any one, wherein Z¹And Z²It is ehter bond, ester independently of one another Key, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the alkylidene of group, singly-bound or Alkylidene, and at Z¹And Z²At least one be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or In the case of comprising these keys arbitrary and the alkylidene of group and being connected to multiple constitutional repeating unit, this construction unit Quantity is less than 2.

[9] the hydrophilic polymer derivant of [1] to [8] any one, wherein P is to have alkyl or chemical anti-at end The linear type Polyethylene Glycol of Ying Xing functional group.

[10] the hydrophilic polymer derivant of [9], wherein w be 1 and P by formula (2) represent:

Y-(OCH₂-CH₂)_n- (2)

Wherein Y is the alkyl with 1 to 24 carbon atom；And n is the integer of 3 to 2000.

[11] the hydrophilic polymer derivant of [9], wherein w be 1 and P by formula (3) represent:

X²-Z³-(OCH₂CH₂)_n- (3)

Wherein X²It is different from X¹Chemical reactivity functional group；Z³It it is divalent spacer thing；And n be 3 to 2000 whole Number.

[12] the hydrophilic polymer derivant of [1] to [8] any one, wherein P is to have at end to be different from X¹'s The branched chain type Polyethylene Glycol of alkyl or chemical reactivity functional group.

[13] the hydrophilic polymer derivant of [12], wherein w be 1 and P by formula (4) represent:

Wherein Y is the alkyl with 1 to 24 carbon atom；N is the integer of 3 to 1000；And v is 0 or 2.

[14] the hydrophilic polymer derivant of [12], wherein w be 1 and P by formula (5) represent:

Wherein X²It is different from X¹Chemical reactivity functional group；Z³It it is divalent spacer thing；N is the integer of 3 to 1000；And And v is 0 or 2.

[15] the hydrophilic polymer derivant of [12], wherein w is that v+2 and P is represented by formula (6):

[16] the hydrophilic polymer derivant of [11], [14] and [15] any one, wherein X²Select free active ester groups, Active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, propylene Acidic group, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen The group that amino, hydrazide group and azido are formed.

[17] the hydrophilic polymer derivant of [11], [14] and [15] any one, wherein X²Select free style (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n) The group formed:

[18] the hydrophilic polymer derivant of [11], [14] and [15] any one, wherein Z³It is ehter bond, ester bond, carbon Acid esters key, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the alkylidene of group, singly-bound or alkylene Base, and at Z³It is ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or comprises these keys arbitrary With the alkylidene of group and in the case of being connected to multiple constitutional repeating unit, the quantity of this construction unit is less than 2.

[19] the hydrophilic polymer derivant of [1] to [8] any one, wherein P be have 2 to 8 end number poly- Ethylene glycol, the whole end of Polyethylene Glycol constituting P is each attached to Z¹, and w is equal to the end number of Polyethylene Glycol.

[20] the hydrophilic polymer derivant of [19], wherein P selects free style (r), formula (s), formula (t), formula (u) and formula V group that () is formed:

Wherein n is the integer of 3 to 2000, and when P is represented by formula (r) w be 2, when P is represented by formula (s) w be 3, When P is represented by formula (t) w be 4, when P is represented by formula (u) w be 4 and when P is represented by formula (v) w be 8.

[21] a kind of ring-type benzylidene acetal linking group compound represented by formula (55):

Wherein R¹And R⁶It is hydrogen atom or alkyl independently of one another；R²、R³、R⁴And R⁵Be independently of one another electrophilic or give electricity Sub-substituent group or hydrogen atom；X³And X⁴Can be identical or different, individually chemical reactivity functional group；S is 1 or 2, and t is 0 or 1, And s+t is 1 or 2；And Z¹And Z²It it is the divalent spacer thing being each independently selected.

[22] the ring-type benzylidene acetal linking group compound of [21], wherein s is 1 and t to be 0, R²And R⁵The most solely It is on the spot hydrogen atom, and R³、R⁴And X³-Z¹Substituent constant (σ) summation (Σ σ) meet-0.30≤Σ σ≤1.05.

[23] the ring-type benzylidene acetal linking group compound of [21], wherein s is 1 and t to be 0, R²And R⁵In extremely Few one is above-mentioned substituent group, and R³、R⁴And X³-Z¹Substituent constant (σ) summation (Σ σ) meet-1.71≤Σ σ≤ 0.88。

[24] the ring-type benzylidene acetal linking group compound of [21], wherein s is 1 and t to be 1, or s is 2 also And t is 0, R²And R⁵It is hydrogen atom independently of one another, and R³、R⁴And X³-Z¹Substituent constant (σ) summation (Σ σ) meet- 0.19≤Σσ≤0.57。

[25] the ring-type benzylidene acetal linking group compound of [21], wherein s is 1 and t to be 1, or s is 2 also And t is 0, R²And R⁵In at least one be above-mentioned substituent group, and R³、R⁴And X³-Z¹The summation (Σ of substituent constant (σ) σ) meet-0.98≤Σ σ≤0.48.

[26] the ring-type benzylidene acetal linking group compound of [21] to [25] any one, wherein X³And X⁴Each Independently selected from by active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, maleoyl Imido grpup, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, The group that pi-allyl, vinyl, amino, oxygen amino, hydrazide group, azido and hydroxyl are formed.

[27] the ring-type benzylidene acetal linking group compound of [21] to [26] any one, wherein X³And X⁴Each Select free style (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula L group that (), formula (m), formula (n) and formula (o) are formed:

[28] the ring-type benzylidene acetal linking group compound of [21] to [27] any one, wherein Z¹And Z²Each It is ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group independently, comprises these keys arbitrary and group Alkylidene, singly-bound or alkylidene, and at Z¹And Z²At least one be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, Amido link, secondary amino group or comprise these keys arbitrary and the alkylidene of group and be connected to the situation of multiple constitutional repeating unit Under, the quantity of this construction unit is less than 2.

[29] the ring-type benzylidene acetal linking group compound of [21] to [28] any one, wherein constitutes X³And X⁴ In the functional group of any one comprise protectiveness group.

Advantages of the present invention

According in the hydrophilic polymer derivant with ring-type benzylidene acetal linking group of the present invention, it is possible to The hydrolysis rate of ring-type benzylidene acetal linking group is controlled according to the pH of weak acid environment in life entity, and can be at mesh Selectively hydrophilic polymer chain is desorbed from the medicine etc. being connected to hydrophilic polymer derivant under the pH of mark part.Cause This, by being transported to as target at the biological functionality molecule or pharmaceutical carrier that are connected to hydrophilic polymer derivant Hydrophilic polymer chain it is desorbed, it is possible to be inherently eliminated such as by the hydration layer forming hydrophilic polymer after tissue or site The problem causing the suppression of cellular uptake and endosome effusion, these problems are traditional hydrophilic polymer modified lacking Point.That is, by using hydrophilic polymer derivant in the chemical modification of medicine etc., it is possible to be given only hydrophilic polymer and change The advantage of property, such as the prolongation of the circulation time in the raising of water solubility and bioavailability and blood, and do not hinder medicine The expression of the original function of thing etc..

Further, since in hydrophilic polymer derivant, hydrophilic polymer and ring-type benzylidene linking group Phenyl ring is by stable bonded in life entity, so when hydrolysis it can be avoided that discharge hydrophilic polymer chain or connection Medicine etc. beyond low molecular weight substance, more specifically low-molecular-weight aromatic aldehydes such that it is able to eliminate low molecular weight substance Impact.

Accompanying drawing explanation

Fig. 1 is shown with the formula (29) described in embodiment, formula (32), formula (33), formula (35) and the compound of formula (36), MES heavy water buffer agent at pD 5.5 and 37 DEG C hydrolyzes the result of test.

Fig. 2 is shown with the formula (29) described in embodiment, formula (32), formula (33), formula (35) and the compound of formula (36), HEPES heavy water buffer agent at pD 7.4 and 37 DEG C hydrolyzes the result of test.

Detailed description of the invention

Hereinafter, will be described in the present invention.

Terminology used herein " acetal " means be derived from the ethylidene ether structure of aldehyde and be derived from the ethylidene ether structure of ketone, source From the ethylidene ether structure of ketone i.e. ketal structure.

It 1 and t is the 5 ring 1,3-dioxies penta of 0 that term used herein " cyclic acetal " means that the s in formula (1) is In ring structure and formula (1), s is 1 and t to be 1 or s to be 2 and t to be the 6 ring 1,3-dioxane structures of 0.

R in the formula (1) of the present invention¹And R⁶Being individually hydrogen atom or hydro carbons group, the amount of carbon atom of hydro carbons group is preferred It is less than 10, and the instantiation of hydro carbons group includes methyl, ethyl, propyl group, isopropyl, the tert-butyl group, phenyl and benzyl. R¹Preferred implementation be hydrogen atom or methyl, and more preferably hydrogen atom.

Phenyl ring in the formula (1) of the present invention can have multiple substituent group.By properly selecting benzene ring substituents Kind, position and give electronic property and the degree of electron withdrawing properties, the hydrolysis affecting cyclic acetal linking group can be regulated The electron density of the acetal radical periphery of speed and sterically hindered degree.It is preferable that this makes it can give cyclic acetal linking group Hydrolysis rate.

In this manual, using " substituent constant (σ) " to describe the substituent group on the phenyl ring in formula (1), substituent group is normal Number means to quantify substituent group to the reaction rate of benzene derivative or the Hammett's rule (Hammett's rule) of the impact of balance In substituent constant.But, as it is known, Hammett's rule is only applied to para-orientation and the substituted benzene derivative of meta, And may not apply to the substituted benzene derivative in the ortho position by sterically hindered impact.Therefore, the substituted benzene derivative at ortho position In the case of, substituent constant means the replacement extending in tower husband's off-square journey (Taft's equation) of above-mentioned Hammett's rule Fundamental constant.

In the substituted benzene derivative of above-mentioned para-orientation and meta, Hammett's rule is represented by below equation (7):

log(k/k₀)=ρ σ (7)

Wherein k is the speed constant of arbitrarily reaction or equilibrium constant, the k of para-orientation and the substituted benzene derivative of meta₀ Be benzene derivative, not there is any substituent group, speed constant in the case of i.e. substituent group is hydrogen atom or equilibrium constant, ρ is Reaction constant, and σ is substituent constant.

Reaction constant (ρ) in above-mentioned formula (7) is depending on the reaction condition of such as response type, temperature or solvent and determines Constant, and can calculate from the slope of Hammett figure (Hammett plot).In the present invention, there is ring-type benzylidene In the acid hydrolytic reaction of the hydrophilic polymer derivant of acetal linking group, in the case of DOX structure, should The result of the hydrolysis test that constant is carried out from the compound of the formula (29) described in embodiment, formula (32) and formula (33) calculates For " ρ=-2.7 ".And, 1, in the case of 3-dioxane structure, this constant is to formula (35) and the compound of formula (36) The result of the hydrolysis test carried out is calculated as " ρ=-4.8 ".

Substituent constant (σ) in above-mentioned formula (7) is to be only dependent upon the type of substituent group and constant that position determines, and instead Answer type unrelated.In the case of there is not substituent group, i.e. substituent group is hydrogen atom, this constant is " 0 ".Description uses Term " electrophilic " mean σ be on the occasion of situation, and term " to electronics " means that σ is the situation of negative value.

As it has been described above, Hammett's rule is only applied to para-orientation or the substituted benzene derivative of meta, and can not apply In the situation by the substituted benzene derivative in the sterically hindered ortho position affected.Therefore, tower husband off-square journey is by this sterically hindered Affect the location constant (Es) as positional factor, i.e. substituent group to introduce, to extend Hammett's rule so that it is neighbour can be applied to The situation of the substituted benzene derivative in position.Tower husband's off-square journey is represented by below equation (8).

log(k/k₀)=ρ * σ *+Es (8)

Wherein k is the speed constant of arbitrarily reaction or equilibrium constant, the k of para-orientation or the substituted benzene derivative of meta₀ Be benzene derivative, not there is any substituent group, speed constant in the case of i.e. substituent group is hydrogen atom or equilibrium constant, ρ * Being reaction constant, σ * is substituent constant, and Es is the location constant of substituent group.

As it is known, due to para-orientation or the reaction constant (ρ) of the substituted benzene derivative of meta and ortho position substituted benzene The reaction constant (ρ *) of derivant is substantially equal, and defined in description, ρ with ρ * is identical.Substituent constant (σ *) due to ortho position Similar to the substituent constant of para-position, such as described in " Charton, M.Can.J.Chem.1960,38 2493-2499 " , in the description, the corresponding substituent constant of para-position is applied to the substituent constant at ortho position.

At " Hansch, C.；Leo,A.；Taft, R.W.Chem.Rev.1991,91,165-195 " in describe para-position and The substituent constant (σ) of meta, and for the substituent group of substituent constant (σ) the unknown, this constant can pass through Method described in " Hammett, L.P.Chem.Rev.1935,17 (1), 125-136 " is measured and determines.Additionally, “Unger,S.H.；Hansch, C.Prog.Phys.Org.Chem.1976,12,91-118 " in describe location constant (Es). But, for the Es used in description, hydrogen atom is defined as " 0 ".

In formula (1), in the case of there is multiple substituent group on phenyl ring, definition additivity is by its substituent constant (σ) Established with location constant (Es), and the summation of σ is represented by " Σ σ " and the summation of Es is represented by " Σ Es ".

Z¹It is connected to the phenyl ring of ring-type benzylidene acetal, and P-Z¹Also it is the substituent group of phenyl ring.P-Z¹Substituent group normal Number can pass through to measure respectively composition and the degree of polymerization of P, and by itself and Z¹Combination determines, but is because P-Z¹Substituent group normal Number is substantially affected greatly by phenyl ring coupling part peripheral structure, and the effect of other parts is the least such that it is able to ignore.Therefore, The known substituent constant of the structure similar to phenyl ring coupling part peripheral structure can be used, replace measuring respectively P-Z¹'s Substituent constant.

As defined herein, it is possible to use and wherein replace except being connected to from P-Z with hydrogen atom¹The skeletal atom of main chain The substituent constant of the structure of the atom beyond second atom of the 3rd atom of the atom computing that phenyl ring connects, replaces P-Z in description¹Substituent constant.But, in the case of forming carboxyl with hydrogen atom replacement atom, defined It is possible to use the substituent constant of the structure wherein replacing atom with methyl replacement hydrogen atom, replace P-Z¹Replacement Fundamental constant.

P-Z¹The structure of phenyl ring coupling part and be shown below for the instantiation of substituted structure.Show below In the case of (r1) that go out, wherein P-Z¹Phenyl ring coupling part be ehter bond, the substituent constant of (r2) that application is illustrated below. In the case of (r3) and (r5) that be shown below, wherein P-Z¹Phenyl ring coupling part be amido link, application is shown below respectively (r4) and the substituent constant of (r6) gone out.In the case of (r7) that be shown below, wherein P-Z¹Phenyl ring coupling part be Amino-formate bond, the substituent constant of (r8) that application is illustrated below.

The hydrophilic polymer derivant with ring-type benzylidene acetal linking group suitable about the present invention Hydrolysis rate, the hydrolysising half-life (t in the buffer agent of pH 5.5 and 37 DEG C_1/2) it is preferably the scope at 1 hour to 6 months In, more preferably 1 hour to 1 month in the range of, and also more preferably in the range of 1 hour to 24 hour.At this In description, use is derived from the numerical value of the compound of the formula (32) described in embodiment, the wherein t under the conditions of said hydrolyzed_1/2 It is 12 hours, thus defines summation (Σ σ) suitable including the substituent constant in the case of DOX structure Scope.Log (k/k when the compound using above-mentioned equation (7) calculating formula (32)₀) time, it is thus achieved that below equation (9).So And, the P-Z according to defined above, in the compound of formula (32)¹With ethyoxyl (CH₃CH₂O-) replace.

log(k/k₀)=-2.7 × (0.34-0.24)=-0.27 (9)

R in formula (1)²And R⁵In the case of being hydrogen atom, above equation (9) and (7) is used to take t_1/2Be 24 little constantly Speed constant calculate log (k'/k as k'₀) time, it is thus achieved that below equation (10).

Log (k'/k)=log{ (12/24) k/k}=-0.30

Deformation the equation,

Log (k'/k)=log [(k'/k₀)/(k/k₀)]=-0.30

log(k'/k₀)-log(k/k₀)=-0.30

Above formula (9) is substituted into,

log(k'/k₀)-(-0.27)=-0.30

log(k'/k₀)=-0.57 (10)

Herein, as summation (the Σ σ) using above equation (10) and equation (7) to calculate substituent constant, it is thus achieved that with Lower equation (11).

log(k'/k₀)=-2.7 × Σ σ=-0.57

Σ σ=0.21 (11)

Similarly, the R in formula (1)²And R⁵In the case of being hydrogen atom, when taking t_1/2It is that 1 little speed constant constantly is made For k " calculate log (k "/k₀) time, it is thus achieved that below equation (12).

Log (k "/k)=log (12k/k)=1.08

Deformation the equation,

Log (k "/k)=log [(k "/k₀)/(k/k₀)]=1.08

log(k"/k₀)-log(k/k₀)=1.08

Above formula (9) is substituted into,

log(k"/k₀)-(0.27)=1.08

log(k"/k₀)=0.81 (12)

Herein, as summation (the Σ σ) using above equation (12) and equation (7) to calculate substituent constant, it is thus achieved that with Lower equation (13).

log(k"/k₀)=-2.7 × Σ σ=0.81

Σ σ=-0.30 (13)

From equation (11) and equation (13), include DOX structure and R in formula (1)²And R⁵It is the feelings of hydrogen atom Under condition, when the scope of Σ σ meets-0.30≤Σ σ≤0.21, the t of hydrophilic polymer derivant_1/2It is 1 hour≤t_1/2≤ 24 hours.Similarly, at 1 hour≤t_1/2≤ 1 month and 1 hour≤t_1/2The Σ σ scope calculated when≤6 months draws respectively Below: 1 hour≤t_1/2-0.30≤Σ σ≤0.76 when≤1 month, 1 hour≤t_1/2-0.30≤Σ σ≤1.05 when≤6 months.

Can be used in the substituent group in the present invention is ring-type in the building-up process not suppressing hydrophilic polymer derivant The acetalation of benzylidene acetal linking group compound, ring-type benzylidene acetal linking group compound and hydrophilic The coupling reaction of intermediate polymer and the substituent group of the functional end-group conversion reaction of hydrophilic polymer derivant, and And the most do not suppress the binding reaction of hydrophilic polymer derivant and medicine etc..

Substituent group can be arbitrary electron-withdrawing substituent and give electron substituent group, as long as it meets above-mentioned condition, And substituent group can be used alone or is applied in combination.Electron-withdrawing substituent includes having the acyl group of 2 to 5 carbon atoms, have 2 To 5 carbon atoms alkoxy carbonyl, have 2 to 5 carbon atoms carbamyl, have 2 to 5 carbon atoms acyloxy, The amide groups with 2 to 5 carbon atoms, the alkoxycarbonyl amino with 2 to 5 carbon atoms, fluorine atom, chlorine atom, bromine are former Son, atomic iodine, there is the alkyl thiol of 1 to 4 carbon atom, there is the alkyl sulphonyl of 1 to 4 carbon atom, there are 6 to 10 The aryl sulfonyl of carbon atom, nitro, trifluoromethyl, cyano group, and its preferred embodiment includes acetyl group, methoxycarbonyl, first Base carbamyl, acetoxyl group, acetamido, methyloxycarbonylamino, fluorine atom, chlorine atom, bromine atoms, atomic iodine, methyl Sulfydryl, benzenesulfonyl, nitro, trifluoromethyl and cyano group.The alkyl with 1 to 4 carbon atom is included to electron substituent group, and Its preferred embodiment includes methyl, ethyl, propyl group, isopropyl and the tert-butyl group.As being in the electron-withdrawing group of meta and being in para-position Include there is the alkoxyl of 1 to 4 carbon atom, there is the virtue of 6 to 10 carbon atoms with the substituent group of the electron donating group facing position Base and there is the aryloxy group of 6 to 10 carbon atoms, and its preferred embodiment includes methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen Base, tert-butoxy, phenyl and phenoxy group.

1,3-dioxolane structure and R is included in formula (1)²And R⁵At least one be the substituent group beyond hydrogen atom In the case of, by using at the minimum fluorine of the maximum phenyl of the impact of above-mentioned substituent group neutral body steric hindrance and sterically hindered impact The location constant (Es) of atom, uses tower husband's off-square journey (8) to calculate respectively at 1 hour≤t_1/2≤ 24 hours, 1 hour≤t_1/2≤ 1 month and 1 hour≤t_1/2≤ 6 months scopes of Σ σ in the buffer agent of pH 5.5 and 37 DEG C, result is as follows: 1 Hour≤t_1/2≤ 24 little constantly ,-1.71≤Σ σ≤0.04, at 1 hour≤t_1/2When≤1 month ,-1.71≤Σ σ≤0.59, And at 1 hour≤t_1/2When≤6 months ,-1.71≤Σ σ≤0.88.

1,3-dioxolane structure and R is included in formula (1)²And R⁵In the case of being hydrogen atom, such as, describe below At 1 hour≤t_1/2≤ 24 little preferred implementations meeting-0.30≤Σ σ≤0.21 constantly.But, replacement shown herein Base means R³And R⁴And according to replacement P-Z defined above¹The structure used.In a preferred embodiment, in formula (1) One meta is methoxyl group, ethyoxyl or acetamido, and more preferably ethyoxyl or acetamido.The most real at another Executing in mode, the para-position in formula (1) is methoxy or ethoxy, and meta is independently selected from by fluorine atom, chlorine former Substituent group in the group that son, bromine atoms and atomic iodine are formed, and more preferably para-position is methoxyl group and a meta is fluorine Atom or chlorine atom.Another preferred embodiment in, para-position in formula (1) and in meta are methoxyl group, ethoxy Base or acetamido, and more preferably methoxy or ethoxy.

Additionally, include DOX structure and R in formula (1)²And R⁵At least one be the replacement beyond hydrogen atom In the case of base, such as, describe below at 1 hour≤t_1/2≤ 24 little preferred realities meeting-1.71≤Σ σ≤0.04 constantly Execute mode.But, substituent group shown herein means R³And R⁴And according to replacement P-Z defined above¹The structure used.? R in formula (1)²And R⁵In one be fluorine atom, methyl or ethyl and in the case of another is hydrogen atom, para-position is preferred For ethyoxyl or acetamido, and more preferably ethyoxyl.R in formula (1)²And R⁵In one be methoxyl group and another In the case of one is hydrogen atom, para-position is preferably selected from the substituent group in the group being made up of methoxyl methyl and acetamido, And more preferably acetamido.

Additionally, use the numerical value of the compound being derived from the formula (35) described in embodiment, wherein pH 5.5 and 37 DEG C Hydrolysising half-life (t in buffer agent_1/2) it is 24 hours, it is possible to limitation type (1) includes 1, in the case of 3-dioxane structure The suitable scope of the summation (Σ σ) of substituent constant.

1,3-dioxane structure and R is included in formula (1)²And R⁵In the case of being hydrogen atom, Σ σ scope meet- During 0.19≤Σ σ≤0.10, the t of hydrophilic polymer derivant_1/2It is 1 hour≤t_1/2≤ 24 hours.Similarly, at 1 hour ≤t_1/2≤ 1 month and 1 hour≤t_1/2The Σ σ scope calculated when≤6 months draws following respectively: 1 hour≤t_1/2≤ 1 -0.19≤Σ σ≤0.41 during the moon, 1 hour≤t_1/2-0.19≤Σ σ≤0.57 when≤6 months.

It addition, include 1 in formula (1), 3-dioxane structure and R²And R⁵At least one be the replacement beyond hydrogen atom In the case of base, by using the phenyl affecting maximum and sterically hindered impact in above-mentioned substituent group neutral body steric hindrance minimum The location constant (Es) of fluorine atom, use tower husband's off-square journey (8) to calculate respectively at 1 hour≤t_1/2≤ 24 hours, 1 hour≤ t_1/2≤ 1 month and 1 hour≤t_1/2≤ 6 months scopes of Σ σ in the buffer agent of pH 5.5 and 37 DEG C.Result is the most such as Under: at 1 hour≤t_1/2≤ 24 little constantly ,-0.98≤Σ σ≤0.00, at 1 hour≤t_1/2When≤1 month ,-0.98≤Σ σ≤ 0.31, and at 1 hour≤t_1/2When≤6 months ,-0.98≤Σ σ≤0.48.

As it has been described above, be suitable for giving the hydrophilic polymer with ring-type benzylidene acetal linking group of the present invention The type of the substituent group of the desired hydrolysis ability of derivant and position can carry out above-mentioned by using equation (7) and equation (8) Calculate and reasonably set.

To the X in the formula (1) of the present invention¹Be not particularly limited, if its be by with the example as chemical modification target Protein, peptide, antibody, nucleic acid or low-molecular-weight drug or the medicine of such as liposome and polymeric micellar such as physiologically active Present in the biological functionality molecule of carrier, functional group reactions forms the functional group of covalent bond.Such as, functional group includes At " Harris, J.M.Poly (Ethylene Glycol) Chemistry；Plenum Press:New York,1992”、 “Hermanson,G.T.Bioconjugate Techniques,2nd ed.；Academic Press:San Diego,CA, 2008 " and " PEGylated Protein Drugs:Basic Science and Clinical Applications； Veronese,F.M.,Ed.；Birkhauser:Basel, Switzerland, 2009 " etc. described in functional group.

X¹Preferred example include active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, Epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, α-halogen For acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen amino, hydrazide group and azido.More specifically, it is possible to by with life It is active ester groups, active carbonic acid ester group, aldehyde radical, isocyanates that the amino reaction of thing functionality molecule forms the functional group of covalent bond Base, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy or carboxyl, it is possible to logical Cross that react the functional group of formation covalent bond with the sulfydryl of biological functionality molecule be active ester groups, active carbonic acid ester group, aldehyde radical, different Cyanic acid ester group, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, Sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl or vinyl, it is possible to by with biological functionality molecule It is sulfydryl, amino, oxygen amino or hydrazide group that aldehyde radical or carboxyl reaction form the functional group of covalent bond, it is possible to by with biological official's energy Property molecule alkynyl reaction to form the functional group of covalent bond be sulfydryl or azido, and can by with biological functionality molecule Azido reaction formed covalent bond functional group be alkynyl.

Term " active ester " referred to herein refers to the activated carbonyl represented by formula :-C (=O)-L, wherein L represent from Remove group.The leaving group represented by L includes succinimido epoxide, phthalimide-based epoxide, 4-Nitrobenzol oxygen Base, 1-imidazole radicals, phenyl-pentafluoride epoxide, benzotriazole-1-base epoxide and 7-azepine benzotriazole 1-base-epoxide etc..Institute herein The term " activated carbon acid esters " claimed refers to the activated carbonate base represented by formula :-O-C (=O)-L, and L represents and above-mentioned phase Same leaving group.

The present invention preferred embodiment in, X¹It is by group (I), group (II), group (III), group (IV) Or the group that group (V) represents.

Group (I): can be by reacting the functional group forming covalent bond with the amino of biological functionality molecule

Following (a), (b), (c), (d), (e) and (f)

Group (II): can be by reacting the functional group forming covalent bond with the sulfydryl of biological functionality molecule

Following (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j)

Group (III): can be by forming the functional group of covalent bond with the aldehyde radical or carboxyl reaction of biological functionality molecule

Following (g), (k), (l) and (m)

Group (IV): can be by reacting the functional group forming covalent bond with the alkynyl of biological functionality molecule

Following (g), (k), (l), (m) and (n)

Group (V): can be by reacting the functional group forming covalent bond with the azido of biological functionality molecule

Following (j)

In above formula, R⁷Being hydrogen atom or sulfo group, the instantiation of sulfo group includes sodium sulfonate and potassium sulfonate, and R⁷Preferably For hydrogen atom.R⁸And R¹¹It is individually hydrogen atom or there is the alkyl of 1 to 5 carbon atom, and the instantiation of alkyl includes first Base, ethyl, propyl group, isopropyl, butyl, the tert-butyl group and amyl group.R⁹Be there is 1 to 10 carbon atom can comprise halogen atom Alkyl, and the instantiation of alkyl include methyl, ethyl, propyl group, isopropyl, butyl, the tert-butyl group, amyl group, isopentyl, oneself Base, benzyl, 4-aminomethyl phenyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-(trifluoromethoxy) phenyl, vinyl, chloroethene Base, bromoethyl and iodine ethyl, and R⁹It is preferably methyl, vinyl, 4-aminomethyl phenyl or 2,2,2-trifluoroethyl.R¹⁰It is to be selected from The halogen atom of chlorine atom, bromine atoms and atomic iodine.

Z in the formula (1) of the present invention¹It is between the phenyl ring and hydrophilic polymer chain of ring-type benzylidene acetal radical Divalent spacer thing, and Z²It is functional group X¹And between ring-type benzylidene acetal radical divalent spacer thing.They are by covalent bond Form and be not particularly limited, as long as they are more more stable than ring-type benzylidene acetal radical to acid hydrolysis, and preferably Be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the Asia of group Alkyl, singly-bound or alkylidene.The amount of carbon atom of alkylidene is preferably from 1 to 24.For convenience of description and it is not any limitation as, The preferred embodiment of alkylidene includes such as the structure of (z1).The preferred example of the alkylidene with ehter bond include such as (z2) or (z3) structure.The preferred example of the alkylidene with ester bond includes such as the structure of (z4).There is the alkylene of carbonic acid ester bond The preferred example of base includes such as the structure of (z5).The preferred example of the alkylidene with urethane bonds includes all Structure such as (z6).The preferred example of the alkylidene with amido link includes such as the structure of (z7).There is the Asia of secondary amino group The preferred example of alkyl includes such as the structure of (z8).In a preferred embodiment, p and q is 1 to 12 independently of one another Integer.Such as, connection functional group X it is being intended in the hydrophobic environment of such as protein interior¹In the case of, p and q is preferably Greatly, and be intended in hydrophilic environments connect functional group X¹In the case of, p and q is the least.But, at Z¹And Z²Extremely Few one is ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or comprises these keys arbitrary and group Alkylidene and in the case of being connected to multiple constitutional repeating unit, the quantity of said structure unit is less than 2.

P in the formula (1) of the present invention is hydrophilic polymer, and its instantiation includes poly alkylene glycol, gathers Oxazoline, Merlon, polyurethane, polyvinyl alcohol, polyacrylate, polymethacrylates, polyacrylamide, polyvinyl pyrrole Alkanone, polylactic acid, polyglycolic acid, polyamino acid and be derived from the copolymer of above polymer, and P is preferably polyalkylene two Alcohol, more preferably Polyethylene Glycol.

Terminology used herein " Polyethylene Glycol " means that the molecular weight with the polymerization acquisition by ethylene oxide divides The Polyethylene Glycol of cloth and the oligoethylene glycol with unimodal molecular weight connect the list distribution Polyethylene Glycol obtained by coupling reaction Both.

In one aspect of the invention, the P in formula (1) is linear type Polyethylene Glycol.

In this regard preferred embodiment in, the P in formula (1) by formula (2) represent.

Y-(OCH₂CH₂)_n- (2)

In the formula, n is the quantity of the repetitive of each polyglycol chain, and has the poly-second of molecular weight distribution In glycol, definition n is that number average molecular weight (Mn) based on compound is obtained by various Theoretical Calculation.

In the formula, Y is the alkyl with 1 to 24 carbon atom, and its instantiation includes methyl, ethyl, propyl group, isopropyl Base, butyl, the tert-butyl group, amyl group, isopentyl, hexyl, heptyl, 2-ethylhexyl, octyl group, nonyl, decyl, undecyl, 12 Alkyl, tridecyl, myristyl, pentadecyl, cetyl, heptadecyl, octadecyl, nonadecyl, eicosyl, Heneicosyl, docosyl, tricosyl, tetracosyl, phenyl, benzyl, tolyl, butyl phenyl, 12 Alkyl phenyl and trityl, and Y preferably has the alkyl of 1 to 10 carbon atom, more preferably methyl or ethyl, the most more It is preferably methyl.

In this regard another preferred embodiment in, the P in formula (1) by formula (3) represent.

X²-Z³-(OCH₂CH₂)_n- (3)

In the formula, X²It is different from X¹Chemical reactivity functional group, and Z³It is at functional group X²And polyglycol chain Between bivalence junctional complex.Owing to polyethyleneglycol derivative has two different chemical reactivity functional group X¹And X², it is permissible There is provided the Polyethylene Glycol-drug conjugate with goal directness matter, such as by medicine is connected to X¹And target is referred to It is connected to X to molecule²。

X²Preferred example include active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, Epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, α-halogen For acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen amino, hydrazide group and azido.More specifically, it is possible to by with life It is active ester groups, active carbonic acid ester group, aldehyde radical, isocyanates that the amino reaction of thing functionality molecule forms the functional group of covalent bond Base, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy or carboxyl, it is possible to logical Cross that react the functional group of formation covalent bond with the sulfydryl of biological functionality molecule be active ester groups, active carbonic acid ester group, aldehyde radical, different Cyanic acid ester group, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, Sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl or vinyl, it is possible to by with biological functionality molecule It is sulfydryl, amino, oxygen amino or hydrazide group that aldehyde radical or carboxyl reaction form the functional group of covalent bond, it is possible to by with biological official's energy Property molecule alkynyl reaction to form the functional group of covalent bond be sulfydryl or azido, and can by with biological functionality molecule Azido reaction formed covalent bond functional group be alkynyl.

The present invention preferred embodiment in, X²It is by group (I), group (II), group (III), group (IV) Or the group that group (V) represents.

Following (a), (b), (c), (d), (e) and (f)

Following (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j)

Following (g), (k), (l) and (m)

Following (g), (k), (l), (m) and (n)

Following (j)

It is necessary that X²It is different from X¹.As X¹And X²The preferred embodiment of combination, work as X¹It is active ester groups or active carbonic acid During ester group, X²It is selected from dimaleoyl imino, vinyl sulfuryl, alpha-halogen acetyl group, alkynyl and the group of azido；Work as X¹It is During aldehyde radical, X²It is selected from dimaleoyl imino, vinyl sulfuryl, alkynyl and the group of azido；Work as X¹Be dimaleoyl imino, When vinyl sulfuryl or alpha-halogen acetyl group, X²It is selected from active ester groups, active carbonic acid ester group, alkynyl and the group of azido； Work as X¹When being alkynyl or azido, X²It is selected from dimaleoyl imino, vinyl sulfuryl, alpha-halogen acetyl group, active ester groups, work Property carbonate group, amino and the group of oxygen amino；Work as X¹When being amino or oxygen amino, X²It is alkynyl, azido, sulfydryl or carboxyl； And work as X¹When being sulfydryl, X²It is selected from amino, oxygen amino, azido and the group of carboxyl.It is highly preferred that work as X¹It it is active ester When base or active carbonic acid ester group, X²It is selected from dimaleoyl imino, alpha-halogen acetyl group, alkynyl and the group of azido；Work as X¹It is During aldehyde radical, X²It is selected from dimaleoyl imino, alpha-halogen acetyl group, alkynyl and the group of azido；Work as X¹It it is dimaleoyl imino Or during alpha-halogen acetyl group, X²It is selected from active ester groups, active carbonic acid ester group, alkynyl and the group of azido；Work as X¹Be alkynyl or During azido, X²It is selected from dimaleoyl imino, alpha-halogen acetyl group, active ester groups, active carbonic acid ester group, amino and oxygen amino Group；Work as X¹When being amino or oxygen amino, X²It is alkynyl, azido or sulfydryl；And work as X¹When being sulfydryl, X²It is selected from ammonia Base, oxygen amino and the group of azido.

Z³It is made up of covalent bond and is not particularly limited, as long as it is more steady than ring-type benzylidene acetal radical to acid hydrolysis Fixed, and preferably ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise arbitrary this A little keys and the alkylidene of group, singly-bound or alkylidene.The amount of carbon atom of alkylidene is preferably from 1 to 24.For convenience of description And not being any limitation as, the preferred embodiment of alkylidene includes such as the structure of (z1).There is the preferred reality of the alkylidene of ehter bond Example includes such as (z2) or the structure of (z3).The preferred example of the alkylidene with ester bond includes such as the structure of (z4).Tool The preferred example having the alkylidene of carbonic acid ester bond includes such as the structure of (z5).There is the alkylidene of urethane bonds Preferably example includes such as the structure of (z6).The preferred example of the alkylidene with amido link includes such as the knot of (z7) Structure.The preferred example of the alkylidene with secondary amino group includes such as the structure of (z8).In a preferred embodiment, p and q is each From the integer being 1 to 12 independently.Such as, connection functional group X it is being intended in the hydrophobic environment of such as protein interior²'s In the case of, p and q is preferably big, and is being intended in hydrophilic environments connection functional group X²In the case of, p and q is preferably Little.But, at Z³It is ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or comprises these keys arbitrary With the alkylidene of group and in the case of being connected to multiple constitutional repeating unit, the quantity of said structure unit is less than 2.

P in another aspect of the present invention, formula (1) is branched polyethylene glycol.

In this regard preferred embodiment in, the P in formula (1) by formula (4) represent.

In the formula, Y is the alkyl as above with 1 to 24 carbon atom, and v is 0 or 2.

In the case of v is 0, there are two polyglycol chains, and in the case of v is 2, there are four Polyethylene Glycol Chain.In general, with in the Polyethylene Glycol chemical modification to bio-related substance, when introducing more than the Polyethylene Glycol needed During junction point, destroy the avtive spot of bio-related substance thus reduce its function, therefore carried out by increasing poly-second two The molecular weight of alcohol improves the trial of effect.But, viscosity increases along with the increase of molecular weight, and the most such as, as The operation of the aqueous solution dosage form of such as injection type becomes difficulty.Owing to polyethyleneglycol derivative has ramiform structure, with tool The linear type polyethyleneglycol derivative having same molecular amount is compared, and it demonstrates low viscosity, therefore in such as aqueous solution dosage form Application is useful.

In this regard another preferred embodiment in, the P in formula (1) by formula (5) represent.

In the formula, X²It is to be different from X as above¹Chemical reactivity functional group, Z³It is between bivalence as above Parting, and v is 0 or 2.

Polyethyleneglycol derivative has an X¹With two or four X², and such as it is connected to X when medicine¹And target Director molecules is connected to X²Time, it is possible to obtain high goal directness energy.

In this regard another preferred embodiment in, the P in formula (1) by formula (6) represent.

In antibody-drug conjugates (ADC) association area, transport efficiency, preferably by multiple to improve medicine Medicine is connected to antibody, but when introducing multiple junction point in antibody, with the affinity of antigen be declined to become problem.Poly- Ethylene glycol derivative has two or four X¹With an X², and such as in the ADC of target on cancer, when anticancer agent connects To X¹And antibody is connected to X²Time, the transport efficiency of anticancer agent can be improved while not increasing the junction point of antibody.

P in an additional aspect of the present invention, formula (1) is the Polyethylene Glycol of the end number with 2 to 8, constitutes the poly-of P The whole end of ethylene glycol is each incorporated into Z¹, and w is equal to the end number of Polyethylene Glycol.

In this regard preferred embodiment in, the P in formula (1) select free style (r), formula (s), formula (t), formula (u) and The group that formula (v) is formed.In the case of P is represented by formula (r), w is 2, and in the case of P is represented by formula (s), w is 3, at P by formula T () represents in the case of, w is 4, and in the case of P is represented by formula (u), w is 4, and w is in the case of P is represented by formula (v) 8。

The preferred scope of the n in the formula (2) of the present invention and (3) is from 3 to 2000, more preferably from 20 to 1500, the most more It is preferably from 40 to 1000, and most preferably from 60 to 500.It addition, the preferred scope of the n in formula (4), formula (5) and formula (6) It is from 3 to 1000, is preferably from 10 to 800, more preferably from 20 to 500, and most preferably from 30 to 300.

According to another aspect of the present invention, it is provided that a kind of ring-type benzylidene acetal linker represented by formula (55) Dough compound.

R in the formula (55) of the present invention¹And R⁶Being individually hydrogen atom or hydro carbons group, the amount of carbon atom of hydro carbons group is excellent Elect as less than 10 and the instantiation of hydro carbons group include methyl, ethyl, propyl group, isopropyl, the tert-butyl group, phenyl and benzene first Base.R¹Preferred implementation be hydrogen atom or methyl, and more preferably hydrogen atom.

Phenyl ring in the formula (55) of the present invention can have multiple substituent group.By properly selecting benzene ring substituents Kind, position and give electronic property and the degree of electron withdrawing properties, the hydrolysis affecting cyclic acetal linking group can be adjusted The electron density of the acetal radical periphery of speed and sterically hindered degree.It is preferable that this makes it can give cyclic acetal linking group Hydrolysis rate.

In this manual, using " substituent constant (σ) " to describe the substituent group on the phenyl ring in formula (55), substituent group is normal Number means to quantify substituent group to the reaction rate of benzene derivative or the Hammett's rule (Hammett's rule) of the impact of balance In substituent constant.But, as it is known, Hammett's rule is only applied to para-orientation and the substituted benzene derivative of meta, And may not apply to by the substituted benzene derivative in the sterically hindered ortho position affected.Therefore, the substituted benzene derivative at ortho position In the case of, substituent constant means the replacement extending in tower husband's off-square journey (Taft's equation) of above-mentioned Hammett's rule Fundamental constant.

As it is known, due in Hammett's rule para-orientation or the reaction constant (ρ) of the substituted benzene derivative of meta Substantially equal with the reaction constant (ρ *) of ortho position substituted benzene derivatives in tower husband's off-square journey, defined in description, ρ with ρ * is identical. Owing in tower husband's off-square journey, the substituent constant (σ *) at ortho position is similar to the substituent constant of para-position, such as " Charton, M.Can.J.Chem.1960,38 2493-2499 " described in, in the description, should by the corresponding substituent constant of para-position Substituent constant for ortho position.

At " Hansch, C.；Leo,A.；Taft, R.W.Chem.Rev.1991,91,165-195 " in describe para-position and The substituent constant (σ) of meta, and for the substituent group of substituent constant (σ) the unknown, this constant can pass through Method described in " Hammett, L.P.Chem.Rev.1935,17 (1), 125-136 " is measured and determines.Additionally, “Unger,S.H.；Hansch, C.Prog.Phys.Org.Chem.1976,12,91-118 " in describe in tower husband's off-square journey Location constant (Es).But, Es used herein is the Es that hydrogen atom is defined as " 0 ".

In formula (55), in the case of there is multiple substituent group on phenyl ring, definition additivity is by its substituent constant (σ) Established with location constant (Es), and the summation of σ is represented by " Σ σ " and the summation of Es is represented by " Σ Es ".

Z¹It is connected to the phenyl ring of ring-type benzylidene acetal, and X³-Z¹Also it is the substituent group of phenyl ring.X³-Z¹Substituent group Constant can be by measuring X respectively³And Z¹Combination determine, but be because X³-Z¹Substituent constant substantially by phenyl ring even The impact connecing part of its periphery structure is big, and the effect of other parts is the least such that it is able to ignore.Therefore, it is possible to use with phenyl ring even Connect the known substituent constant of the similar structure of part of its periphery structure, replace individually measuring X respectively³-Z¹Substituent constant.

It is defined as in the description, it is possible to use and be wherein connected to from X with hydrogen atom replacement³-Z¹The skeletal atom of main chain The substituent constant of the structure of the atom beyond second atom of the 3rd atom of the atom computing that phenyl ring connects, replaces X³-Z¹Substituent constant.But, replace atom with hydrogen atom and in the case of forming carboxyl, defined in it is possible to make With the substituent constant of the structure wherein replacing hydrogen atom replacement atom with methyl, replace X³-Z¹Substituent constant.Additionally, At X³-Z¹The skeletal atom of main chain be below 4 atoms in the case of, use the known substituent group described in above-mentioned document normal Number, or the value obtained by measuring can be used according to the method described in above-mentioned document.

X³-Z¹The structure of phenyl ring coupling part and be shown below for the instantiation of substituted structure.Show below In the case of (r1) that go out, wherein X³-Z¹Phenyl ring coupling part be ehter bond, the substituent constant of (r2) that application is illustrated below. In the case of (r3) and (r5) that be shown below, wherein X³-Z¹Phenyl ring coupling part be amido link, application is shown below respectively (r4) and the substituent constant of (r6) gone out.In the case of (r7) that be shown below, wherein X³-Z¹Phenyl ring coupling part be Amino-formate bond, the substituent constant of (r8) that application is illustrated below.

Can be used in substituent group in this respect is in the building-up process of ring-type benzylidene acetal linking group compound Do not suppress acetalation and the substituent group of functional end-group conversion reaction, and be not in a preferred embodiment of the invention Suppression linking group compound in addition to above-mentioned reaction and the coupling reaction of hydrophilic polymer intermediate, obtained hydrophilic The functional end-group conversion reaction of property polymer derivant and the binding reaction of hydrophilic polymer derivant and medicine etc. Substituent group.

Substituent group can be arbitrary electron-withdrawing substituent and give electron substituent group, as long as it meets above-mentioned condition, And substituent group can be used alone or is applied in combination.Electron-withdrawing substituent includes having the acyl group of 2 to 5 carbon atoms, have 2 To 5 carbon atoms alkoxy carbonyl matrix, there is the carbamyl of 2 to 5 carbon atoms, there is the acyl-oxygen of 2 to 5 carbon atoms Base, there is the amide groups of 2 to 5 carbon atoms, there is the alkoxycarbonyl amino of 2 to 5 carbon atoms, fluorine atom, chlorine atom, bromine Atom, atomic iodine, there is the alkyl thiol of 1 to 4 carbon atom, there is the alkyl sulphonyl of 1 to 4 carbon atom, have 6 to 10 The aryl sulfonyl of individual carbon atom, nitro, trifluoromethyl, cyano group, and its preferred embodiment include acetyl group, methoxycarbonyl, Methylcarbamoyl, acetoxyl group, acetamido, methyloxycarbonylamino, fluorine atom, chlorine atom, bromine atoms, atomic iodine, first Base sulfydryl, benzenesulfonyl, nitro, trifluoromethyl and cyano group.The alkyl with 1 to 4 carbon atom is included to electron substituent group, and And its preferred embodiment includes methyl, ethyl, propyl group, isopropyl and the tert-butyl group.As be in the electron-withdrawing group of meta and be in right Position includes having the alkoxyl of 1 to 4 carbon atom with the substituent group of the electron donating group facing position, has 6 to 10 carbon atoms Aryl and there is the aryloxy group of 6 to 10 carbon atoms, and its preferred embodiment includes methoxyl group, ethyoxyl, propoxyl group, isopropyl oxygen Base, tert-butoxy, phenyl and phenoxy group.

About the hydrolysis rate of the ring-type benzylidene acetal linking group compound of the present invention, pH 5.5 and 37 DEG C Hydrolysising half-life (t in buffer agent_1/2) be preferably 1 hour to 6 months in the range of, more preferably at 1 hour to 1 month In the range of, and also more preferably in the range of 1 hour to 24 hour.

1,3-dioxolane structure and R is included in formula (55)²And R⁵In the case of being hydrogen atom, preferred substituent group is normal The scope of number summation (Σ σ) was at 1 hour≤t_1/2≤ 24 little satisfied-0.30≤Σ σ≤0.21 constantly, at 1 hour≤t_1/2≤ 1 -0.30≤Σ σ≤0.76 is met during the moon, and at 1 hour≤t_1/2-0.30≤Σ σ≤1.05 are met when≤6 months.

1,3-dioxolane structure and R is included in formula (55)²And R⁵At least one be the substituent group beyond hydrogen atom In the case of, the scope of Σ σ was at 1 hour≤t_1/2≤ 24 little satisfied-1.71≤Σ σ≤0.04 constantly, at 1 hour≤t_1/2≤ 1 -1.71≤Σ σ≤0.59 is met during the moon, and at 1 hour≤t_1/2-1.71≤Σ σ≤0.88 is met when≤6 months.

1,3-dioxolane structure and R is included in formula (55)²And R⁵In the case of being hydrogen atom, such as, describe below At 1 hour≤t_1/2≤ 24 little preferred implementations meeting-0.30≤Σ σ≤0.21 constantly.But, replacement shown herein Base means R³、R⁴And X³-Z¹And according to replacement X defined above³--Z¹The structure used.In a preferred embodiment, formula (55) meta in is methoxyl group, ethyoxyl or acetamido, and more preferably ethyoxyl or acetamido.At another In preferred embodiment, the para-position in formula (55) is methoxy or ethoxy, and a meta is choosing free fluorine atom, chlorine Substituent group in the group that atom, bromine atoms and atomic iodine are formed, and more preferably para-position is methoxyl group and a meta is Fluorine atom or chlorine atom.Another preferred embodiment in, para-position in formula (55) and in meta are methoxyl group, second Epoxide or acetamido, and more preferably methoxy or ethoxy.

Additionally, include DOX structure and R in formula (55)²And R⁵At least one be taking beyond hydrogen atom In the case of Dai Ji, such as, describe below at 1 hour≤t_1/2≤ 24 little constantly meet-1.71≤Σ σ≤0.04 preferred Embodiment.But, substituent group shown herein means R³、R⁴And X³-Z¹And according to replacement X defined above³-Z¹Use Structure.R in formula (55)²And R⁵In one be fluorine atom, methyl or ethyl and in the case of another is hydrogen atom, Para-position is preferably ethyoxyl or acetamido, and more preferably ethyoxyl.R in formula (55)²And R⁵In one be methoxy Base and in the case of another is hydrogen atom, para-position is preferably selected from the group being made up of methoxyl methyl and acetamido Substituent group, and more preferably acetamido.

1,3-dioxane structure and R is included in formula (55)²And R⁵In the case of being hydrogen atom, preferred substituent group is normal The scope of number summation (Σ σ) was at 1 hour≤t_1/2≤ 24 little satisfied-0.19≤Σ σ≤0.10 constantly, at 1 hour≤t_1/2≤ 1 -0.19≤Σ σ≤0.41 is met during the moon, and at 1 hour≤t_1/2-0.19≤Σ σ≤0.57 is met when≤6 months.

It addition, include 1 in formula (55), 3-dioxane structure and R²And R⁵At least one be taking beyond hydrogen atom In the case of Dai Ji, the scope of Σ σ was at 1 hour≤t_1/2≤ 24 little satisfied-0.98≤Σ σ≤0.00 constantly, at 1 hour≤t_1/2 -0.98≤Σ σ≤0.31 is met when≤1 month, and at 1 hour≤t_1/2-0.98≤Σ σ≤0.48 is met when≤6 months.

X in formula (55)³And X⁴It is chemical reactivity functional group independently of one another, and while not intending on limiting linking group The application of compound, in a preferred embodiment of the invention, has the parent of the ring-type benzylidene acetal linking group of formula (1) Waterborne polymeric derivant can pass through X³And the coupling between the chemical reactivity functional group of hydrophilic polymer intermediate Reaction synthesizes.

X in formula (55)³And X⁴Preferred example include active ester groups, active carbonic acid ester group, aldehyde radical, NCO, Isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, two sulfur For pyridine radicals, alpha-halogen acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen amino, hydrazide group, azido and hydroxyl.According to More specifically embodiment, it is possible to form covalent bond by reacting with the amino of complex reaction thing (reaction partner) Functional group is active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, maleimide Base, vinyl sulfuryl, acrylic, sulfonyloxy or carboxyl；Can be by reacting formation altogether with the sulfydryl with complex reaction thing The functional group of valence link is active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, Malaysia Imide, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynes Base, pi-allyl or vinyl；Can be by forming the functional group of covalent bond with the aldehyde radical or carboxyl reaction with complex reaction thing Sulfydryl, amino, oxygen amino or hydrazide group；Can be mercapto by reacting the functional group forming covalent bond with the alkynyl of complex reaction thing Base or azido, it is possible to by with the azido of complex reaction thing react formed covalent bond functional group be alkynyl；And can It is hydroxyl by reacting the functional group forming covalent bond with the haloalkyl of complex reaction thing, alkyl sulfonic ester or aromatic yl sulphonate Base, sulfydryl or amino.

In preferred implementation in this regard, X³And X⁴It is individually by group (I), group (II), group (III), group (IV), the group that group (V) or group (VI) represent.

Group (I): can be by reacting the functional group forming covalent bond with the amino of complex reaction thing

Following (a), (b), (c), (d), (e) and (f)

Group (II): can be by reacting the functional group forming covalent bond with the sulfydryl of complex reaction thing

Following (a), (b), (c), (d), (e), (f), (g), (h), (i) and (j)

Group (III): can be by forming the functional group of covalent bond with the aldehyde radical or carboxyl reaction of complex reaction thing

Following (g), (k), (l) and (m)

Group (IV): can be by reacting the functional group forming covalent bond with the alkynyl of complex reaction thing

Following (g), (k), (l), (m) and (n)

Group (V): can be by reacting the functional group forming covalent bond with the azido of complex reaction thing

Following (j)

Group (VI): can be by reacting shape with the haloalkyl of complex reaction thing, alkyl sulfonic ester or aromatic yl sulphonate Become the functional group of covalent bond

Following (o), (g) and (k)

X³And X⁴Can be same to each other or different to each other.As mutually different X³And X⁴The preferred embodiment of combination, work as X³It is alive When property ester group or active carbonic acid ester group, X⁴It is selected from dimaleoyl imino, vinyl sulfuryl, alpha-halogen acetyl group, alkynyl and to fold The group of nitrilo；Work as X³When being aldehyde radical, X⁴It is selected from dimaleoyl imino, vinyl sulfuryl, alkynyl and the group of azido；When X³When being dimaleoyl imino, vinyl sulfuryl or alpha-halogen acetyl group, X⁴It is selected from active ester groups, active carbonic acid ester group, alkynyl Group with azido；Work as X³When being alkynyl or azido, X⁴It is selected from dimaleoyl imino, vinyl sulfuryl, alpha-halogen acetyl Base, active ester groups, active carbonic acid ester group, amino, oxygen amino and the group of hydroxyl；Work as X³When being amino or oxygen amino, X⁴It is alkynes Base, azido, sulfydryl, hydroxyl or carboxyl；And work as X³When being sulfydryl or hydroxyl, X⁴Be selected from amino, oxygen amino, azido and The group of carboxyl.It is highly preferred that work as X³When being active ester groups or active carbonic acid ester group, X⁴It is selected from dimaleoyl imino, alpha-halogen The group of acetyl group, alkynyl and azido；Work as X³When being aldehyde radical, X⁴It is selected from dimaleoyl imino, alpha-halogen acetyl group, alkynyl Group with azido；Work as X³When being dimaleoyl imino or alpha-halogen acetyl group, X⁴It is selected from active ester groups, activated carbon acid esters The group of base, alkynyl and azido；Work as X³When being alkynyl or azido, X⁴Be selected from dimaleoyl imino, alpha-halogen acetyl group, Active ester groups, active carbonic acid ester group, amino, oxygen amino and the group of hydroxyl；Work as X³When being amino or oxygen amino, X⁴It is alkynyl, folds Nitrilo, hydroxyl or sulfydryl；And work as X³When being sulfydryl or hydroxyl, X⁴It is selected from amino, oxygen amino and the group of azido.

The Z in formula (55) in this respect¹It is at the phenyl ring of ring-type benzylidene acetal radical and functional group X³Between bivalence between Parting, and Z²It is functional group X⁴And between ring-type benzylidene acetal radical divalent spacer thing.They are made up of also covalent bond And be not particularly limited, as long as they are more more stable than ring-type benzylidene acetal radical to acid hydrolysis, and preferably ether Key, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the alkylidene of group, list Key or alkylidene.The amount of carbon atom of alkylidene is preferably from 1 to 24.For convenience of description and be not any limitation as, alkylidene Preferred embodiment include such as the structure of (z1).The preferred example of the alkylidene with ehter bond includes such as (z2's) or (z3) Structure.The preferred example of the alkylidene with ester bond includes such as the structure of (z4).There is alkylidene excellent of carbonic acid ester bond The example of choosing includes such as the structure of (z5).The preferred example of the alkylidene with urethane bonds includes such as (z6) Structure.The preferred example of the alkylidene with amido link includes such as the structure of (z7).There is the alkylidene of secondary amino group Preferably example includes such as the structure of (z8).In a preferred embodiment, p and q is the integer of 1 to 12 independently of one another. But, at Z¹And Z²At least one be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or comprise appoint These keys of meaning and the alkylidene of group and in the case of being connected to multiple constitutional repeating unit, the quantity of said structure unit It is less than 2.

The hydrophilic polymer derivant with ring-type benzylidene acetal linking group of the present invention can be by tool Coupling reaction is carried out between ring-type benzylidene acetal linking group compound and the hydrophilic polymer intermediate of substituted base And synthesize.The key generated by coupling reaction is determined by the combination of the functional group used in reacting, and is between above-mentioned bivalence Parting Z¹In comprise ehter bond, ester bond, carbonic acid ester bond, urethane bonds, amido link, secondary amino group, comprise arbitrary these Key and the alkylidene of group, singly-bound or alkylidene.In the hydrophilic polymer derivant of synthesis, functional end-group is as required Chemical conversion.About the reaction for functional group conversions, it is possible to use conventionally known method, however it is necessary that selecting type rightly (1) ring-type benzylidene acetal radical and above-mentioned divalent spacer thing Z¹And Z²In the condition that is not decomposed of the key that comprises.

Coupling is carried out about between ring-type benzylidene acetal linking group compound and hydrophilic polymer intermediate The representative instance of the chemical conversion of reaction and functional end-group, exemplified with the following step.It is described herein as Exemplary hydrophilic The Polyethylene Glycol of polymer, as an example.

(A) synthesis of ring-type benzylidene acetal linking group compound

Wherein R¹It is hydrogen atom or hydro carbons group；And R²、R³、R⁴And R⁵Be independently of one another electrophilic or to electronics replace Base or hydrogen atom.

Make the carbonyl compound with the formula (14) of the hydroxyl as chemical reactivity functional group and there are adjacent two formyls of benzene The 1,2-diol, derivatives of the formula (15) that the amino of imido grpup is protected by phthalyl is in such as toluene, benzene, dimethylbenzene, second Nitrile, ethyl acetate, Anaesthetie Ether, t-butyl methyl ether, oxolane, chloroform, dichloromethane, dimethyl sulfoxide, dimethyl formyl In the aprotic solvent of amine or dimethyl acetylamide or do not use solvent, react in the presence of acid catalyst to obtain with following formula (16) the compound with ring-type benzylidene acetal groups.Gained compound can be by extraction, recrystallization, adsorbent The purification such as reason or column chromatography.Substitute carbonyl compound, it is possible to use the corresponding acetal derivant of lower alcohol.This lower alcohol is preferably There is the alcohol of 1 to 5 carbon atom, and more preferably methanol or ethanol.Acid catalyst can be organic acid or mineral acid and It is not particularly limited, and its instantiation includes p-methyl benzenesulfonic acid, pyridinium p-toluenesulfonate, methanesulfonic acid, 10-Camphora sulphur Acid, hydrochloric acid, iodine, ammonium chloride, oxalic acid and boron trifluoride-dimethyl ether complex etc..

" blocking group " referred to herein is to stop or hinder specific chemistry in molecule anti-under some reaction condition The composition of the reaction of Ying Xing functional group.Blocking group depends on the type of chemical reactivity functional group to be protected, the bar of use Other functional groups or the existence of blocking group in part and molecule and change.The particular instance of blocking group can be at the common book of many Nationality finds, and such as at " Wuts, P.G.M.；Greene,T.W.Protective Groups in Organic Synthesis,4th ed.；Wiley-Interscience:New York, 2007 " described in.Additionally, be suitable for by using In the reaction condition of various blocking groups, i.e. by there is chemical reaction, it is possible to make the functional group protected by blocking group pass through Deprotect and regenerate original functional group.Therefore, in the description, protected by blocking group and can be gone by various reactions The functional group of protection is included in " chemical reactivity functional group ".The typical deprotection condition of blocking group is documented in above-mentioned document In.

About the chemical reactivity functional group in the compound of formula (14), it is also possible to use the functional group beyond hydroxyl.Its Instantiation includes hydroxyalkyl, amino, aminoalkyl, carboxyl and carboxyalkyl.And, above-mentioned functional group can be protected by blocking group Protecting, this blocking group is at the stable under acidic conditions of acetalation, and can connect decomposing ring-type benzylidene acetal Deprotect under reaction condition beyond the catalysis reduction of group.As functional group to be protected and the preferably group of blocking group Close, when functional group to be protected is hydroxyl or hydroxyalkyl, such as, protect exemplified with monosilane base system blocking group and acyl group system Protect group, and its instantiation includes t-butyldiphenylsilyl, t-butyldimethylsilyl, triisopropyl first Silylation, acetyl group and pivaloyl group.When functional group to be protected is amino or aminoalkyl, such as, exemplified with acyl Base system blocking group and carbamate system blocking group, and its instantiation includes trifluoroacetyl group, 9-fluorenylmethyloxycarbonyl With 2-(trimethyl silyl) carbethoxyl group.When functional group to be protected is carboxyl or carboxyalkyl, such as, exemplified with alkane Base ester system's blocking group and silyl ester system blocking group, and its instantiation includes methyl, 9-fluorene methyl and the tert-butyl group Dimetylsilyl.Type and typical case's deprotection condition of concrete blocking group are recorded in the above documents, and can select Select the reaction condition being suitable for each blocking group, and deprotect can with the reaction of hydrophilic polymer intermediate before Carry out.

Additionally, about in the compound of formula (15) 1, the chemical reactivity functional group outside 2-glycol ingredient, also can Enough use the functional group outside phthalimidyl.In the functional group that chemical reactivity functional group is protected by blocking group In the case of, it is necessary that this blocking group, and can be at Decomposition of benzene methylene at the stable under acidic conditions of acetalation Deprotect under reaction condition beyond the catalysis reduction of base acetal linking group.As functional group to be protected and blocking group Preferred compositions, when functional group to be protected is amino, such as, exemplified with acyl group system blocking group and carbamate system Blocking group, and its instantiation includes trifluoroacetyl group, 9-fluorenylmethyloxycarbonyl and 2-(trimethyl silyl) ethoxy carbonyl Base.When functional group to be protected is hydroxyl, such as, exemplified with monosilane base system blocking group and acyl group system blocking group, And its instantiation include t-butyldiphenylsilyl, t-butyldimethylsilyl, triisopropylsilyl, Acetyl group and pivaloyl group.When functional group to be protected is carboxyl, such as, exemplified with Arrcostab system blocking group and Silyl ester system blocking group, and its instantiation includes methyl, 9-fluorene methyl and t-butyldimethylsilyl.When When functional group to be protected is sulfonyl, such as, exemplified with thioether system blocking group, sulfocarbonate system blocking group and two Sulfide-based blocking group, and its instantiation includes S-2,4-dinitrophenyl, S-9-fluorenylmethyloxycarbonyl and the S-tert-butyl group Disulfide group.The typical deprotection condition of blocking group is recorded in the above documents, and can select to be suitable for each protection group The reaction condition of group.But, even if the most do not suppress acetalation when chemically reactive group is to be not protected radical protection Functional group in the case of, it is not necessary to use blocking group.

(B) synthesis of Polyethylene Glycol intermediate

Using the amount of 3 to 2000 molar equivalents of the methanol as initiator, in toluene or do not use solvent, at such as gold Belong to polymerization oxidation ethylene under the conditions of the alkalescence of sodium, metallic potassium, sodium hydride or hydrofining, to obtain the Polyethylene Glycol of formula (17).Draw Send out agent and preferably there is the alcohol of alkyl of 1 to 24 carbon atom, and specifically include methanol, ethanol, propanol, isopropanol, butanol, The tert-butyl alcohol, phenol and benzyl alcohol.Owing to Polyethylene Glycol has the hydroxyl as chemically reactive group, its can with ring-type benzene The coupling reaction of methylene acetal linking group compound is used as.

CH₃-(OCH₂CH₂)_n-OH (17)

Make the Polyethylene Glycol of formula (17) and mesyl chloride at such as toluene, benzene, dimethylbenzene, acetonitrile, ethyl acetate, diethyl Ether, t-butyl methyl ether, oxolane, chloroform, dichloromethane, dimethyl sulfoxide, dimethylformamide or dimethyl acetylamide In aprotic solvent or do not use solvent, organic at such as triethylamine, N-methylmorpholine, pyridine or 4-dimethylaminopyridine React in the presence of the inorganic base of alkali or such as sodium carbonate, sodium bicarbonate, sodium acetate or potassium carbonate, to obtain the poly-second of formula (18) Diol intermediates.Organic base and inorganic base can not be used.The usage rate of organic base or inorganic base is not particularly limited, and And more than the equimolar amounts of the preferably hydroxyl of the Polyethylene Glycol of formula (17).Furthermore, it is possible to use organic base as solvent.Obtain Compound can pass through such as extraction, recrystallization, sorbent treatment, reprecipitation, column chromatography or the purification side of supercritical extraction Method purification.

About the chemical reactivity functional group in the Polyethylene Glycol intermediate of formula (18), it is also possible to use other functional groups. The preferred embodiment of chemical reactivity functional group is wherein to be connected with above-mentioned ring-type benzylidene acetal by Polyethylene Glycol intermediate The key that the coupling reaction of group compound generates becomes the divalent spacer thing Z of formula (1)¹In comprise ehter bond, ester bond, carbonic ester Key, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the official of the alkylidene of group, singly-bound or alkylidene Can roll into a ball, and specifically include such as halogen atom, active ester, activated carbon acid esters, aldehyde radical, amino, hydroxyl and carboxyl.

(C) ring-type benzylidene acetal linking group compound and the coupling reaction of Polyethylene Glycol intermediate

By the Polyethylene Glycol intermediate of the benzylidene acetal linking group compound of formula (16) and formula (18) in such as first Benzene, benzene, dimethylbenzene, acetonitrile, ethyl acetate, Anaesthetie Ether, t-butyl methyl ether, oxolane, chloroform, dichloromethane, diformazan In the aprotic solvent of sulfoxide, dimethylformamide or dimethyl acetylamide or do not use solvent, at such as triethylamine, N-methyl Morpholine, potassium tert-butoxide or pyridine or the organic base of hmds base sodium or such as potassium carbonate, potassium hydroxide or sodium hydride Coupling reaction is carried out, to obtain the compound of formula (19) in the presence of inorganic base.The usage rate of organic base or inorganic base is not had It is particularly limited to, but more than the equimolar amounts of the preferably chemical reactivity functional group of the Polyethylene Glycol intermediate of formula (18). Furthermore, it is possible to use organic base as solvent.The compound obtained can pass through aforementioned purification process purification.

Can with the coupling reaction of Polyethylene Glycol intermediate before, to ring-type benzylidene acetal linking group compound Chemical reactivity functional group carry out functional group conversions.The reaction condition of coupling reaction depends on that ring-type benzylidene acetal connects The chemical reactivity functional group of group compound and the combination of the chemical reactivity functional group of Polyethylene Glycol intermediate, and can Use conventionally known method.However, it is necessary to rightly between the ring-type benzylidene acetal groups of selecting type (1) and above-mentioned bivalence Parting Z¹And Z²The Undec condition of key comprised.

(D) there is the conversion of the functional end-group of the polyethyleneglycol derivative of ring-type benzylidene acetal linking group

Use such as ethylenediamine, methyl hydrazine or the alkaline organic compound of methylamine or such as hydrazine, azanol or sodium hydroxide Alkaline inorganic compound, in the proton solvent of such as water, methanol or ethanol, or at such as acetonitrile, oxolane, diformazan In the aprotic solvent of sulfoxide, dimethylformamide or dimethyl acetylamide or do not use solvent, process the compound of formula (19), To obtain the compound that wherein phthalimidyl deprotected and be converted into the formula (20) of amino.To alkali compounds Usage rate is not particularly limited, and preferably the chemical reactivity functional group of the compound of formula (19) equimolar amounts with On.Furthermore, it is possible to use alkali compounds as solvent.The compound obtained can pass through aforementioned purification process purification.

It addition, make the compound of formula (20) and N-succinimido-3-maleimidoproprionic acid ester such as toluene, Benzene, dimethylbenzene, acetonitrile, ethyl acetate, Anaesthetie Ether, t-butyl methyl ether, oxolane, chloroform, dichloromethane, diformazan are sub- In the aprotic solvent of sulfone, dimethylformamide or dimethyl acetylamide or do not use solvent, at such as triethylamine, N-methyl The organic base of quinoline, pyridine or 4-dimethylaminopyridine or the inorganic base of such as sodium carbonate, sodium bicarbonate, sodium acetate or potassium carbonate In the presence of react, to obtain the compound that wherein terminad introduces the formula (21) of dimaleoyl imino.Can not use Machine alkali and inorganic base.The usage rate of organic base or inorganic base is not particularly limited, and the compound of preferably formula (20) Chemical reactivity functional group equimolar amounts more than.Furthermore, it is possible to use organic base as solvent.The compound obtained is permissible By aforementioned purification process purification.

Embodiment

With reference to embodiment, it is specifically described the present invention further, but the present invention is not construed as being confined to this A little embodiments.

?¹During H-NMR analyzes, employ JNM-ECP400 or JNM-ECA600 manufactured by JEOL DATUM Ltd..? In measurement, employ the test tube of 5mm φ, and be CDCl at deuterated solvent₃、CD₃CN or CD₃Tetramethyl is used in the case of OD Silane (TMS) is as internal standard substance, or is D at deuterated solvent₂Use HDO as reference material in the case of O.

In gel permeation chromatography (GPC) is analyzed, use SHODEX GPC SYSTEM-11 as GPC system, SHODEX RIX8 is as differential refractometer i.e. detector, and three root chromatogram columns i.e. SHODEX KF801L, KF803L and KF804L (φ 8mm × 300mm) it is connected in series as GPC chromatographic column, and the temperature of column oven is set as 40 DEG C.Use oxolane as eluting Agent measures, and flow velocity is 1mL/min, and sample concentration is 0.1wt%, and sample size is 0.1mL.Use by Kanto Ethylene glycol, diethylene glycol and the 2,2'-ethylenedioxybis(ethanol). of Chemical Co., Ltd. manufacture and the tool manufactured by Polymer Laboratory There are the Polyethylene Glycol of the molecular weight of 600 to 70000 or the GPC Polymer Standards sample of polyethylene glycol oxide, prepare calibration curve.Close In data analysis, employ BORWIN GPC calculation procedure.Mn represents that number average molecular weight, Mw represent weight averaged molecular Measure, and molecular weight distribution is shown as the value of calculation of Mw/Mn.

Based at " Glasoe, P.K.；Long, F.A.J.Phys.Chem.1960,64,188-190 " described in following Relational equation, by MES (MES) the deuterated aqueous solution of 0.1M and 0.1M HEPES (2-[4-(ethoxy)- 1-piperazinyl] ethyl sulfonic acid) deuterated aqueous solution is separately added into the deuterated aqueous solution of sodium hydroxide of 0.1M, it is prepared for respectively for water Solve MES deuterated water buffer agent and the HEPES deuterated water buffer agent of pD 7.4 of the pD 5.5 of test.

The measured value+0.40 of pD=pH meter

By¹H-NMR assesses percent hydrolysis, the integrated value taking the hydrogen of acetal radical and the integration of the hydrogen passing through the aldehyde radical hydrolyzed to form Value, respectively as I¹And I², calculate according to following computing formula.

Percent hydrolysis (%)=[I²/(I¹+I²)]×100

(embodiment 1)

To equipped with thermometer, nitrogen inlet duct, agitator, Dean-stark pipe and the 200mL three-neck flask of condensing tube Middle injection 1,2,6-hexanetriol (30.0g, 0.224mol), acetone dimethyl acetal (25.6g, 0.246mol) and p-methyl benzenesulfonic acid one Hydrate (0.426g, 2.24mmol), carries out reacting distillation simultaneously in 3 hours at 80 DEG C and removes methanol.It is added thereto to triethylamine (0.453g, 4.48mmol) also stirs the mixture for a period of time, with diluted ethyl acetate, and with the sodium chloride of 20 weight % Solution cleans.Organic layer anhydrous sodium sulfate is dried, and after filtration, solvent is removed under reduced pressure distillation.Residue passes through silica gel color Spectrometry purification, to obtain the compound of formula (22).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.35(3H,s,-CH ₃),1.41(3H,s,-CH ₃),1.49-1.67(6H,m,>CHCH ₂CH ₂CH ₂-),2.07(1H, brs,-OH),3.51(1H,t,-OCH ₂CH<),3.64(2H,t,-CH ₂OH),4.04(1H,dd,-OCH ₂CH<),4.07-4.10 (1H,m,-OCH₂CH<)

(embodiment 2)

To equipped with pouring-in in the 500mL four-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (22) Compound (20.0g, 0.115mol), triethylamine (23.3g, 0.230mol) and toluene (200g), be cooled to 10 DEG C by mixture Below.While persistently cooling, the mesyl chloride (19.8g, 0.173mol) being added dropwise over wherein in Dropping funnel.? After being added dropwise over, carry out reacting 2 hours at 20 DEG C.Add ethanol (7.97g, 0.173mol) and stir the mixture for one The section time, then filter.Cleaning organic layer with ion exchange water, be dried with anhydrous sodium sulfate, after filtration, under reduced pressure distillation is gone Except solvent, to obtain the compound of formula (23).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.35(3H,s,-CH ₃),1.40(3H,s,-CH ₃),1.44-1.83(6H,m,>CHCH ₂CH ₂CH ₂-),3.01(3H, s,-OSO₂CH ₃),3.51(1H,t,-OCH ₂CH<),4.03-4.11(2H,m,-OCH ₂CH<,-OCH₂CH<),4.24(2H,t,- CH ₂OSO₂CH₃)

(embodiment 3)

To equipped with pouring-in in the 500mL four-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (23) Compound (20.0g, 79.3mmol), potassium phthalimide (17.6g, 95.2mmol) and dehydration dimethylformamide (200g), carry out reacting 2 hours at 60 DEG C.Mixture is cooled to less than 10 DEG C, is added thereto to ion exchange water (400g) Then stir a period of time, extract this mixture with the mixed solution of ethyl acetate/hexane (60/40v/v).By 0.2 weight % Wet chemical clean organic layer, and be dried with anhydrous sodium sulfate.After filtration, solvent is removed in decompression distillation, to obtain The compound of formula (24).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.34(3H,s,-CH ₃),1.39(3H,s,-CH ₃),1.44-1.75(6H,m,>CHCH ₂CH ₂CH ₂-),3.50(1H, t,-OCH ₂CH<),3.69(2H,t,-CH ₂-phthalimide), 4.01-4.09 (2H, m ,-OCH ₂CH<,-OCH₂CH<), 7.71-7.85 (4H, m ,-phthalimide)

(embodiment 4)

To the change equipped with pouring-in in the 1L four-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (24) Compound (15.2g, 50.0mmol), p-methyl benzenesulfonic acid monohydrate (951mg, 5.00mmol) and methanol (500mL), at room temperature Carry out reacting 4 hours.Being added thereto to triethylamine (1.01g, 10.0mmol) then stir a period of time, decompression distillation is removed molten Agent.Residue is dissolved in chloroform, and solution ion exchange water cleans, and is dried by organic layer anhydrous sodium sulfate.Filter After, decompression distillation removes solvent, to obtain the compound of formula (25).

¹H-NMR(CD₃CN, internal standard substance TMS)；δ (ppm):

1.24-1.61(6H,m,>CHCH ₂CH ₂CH ₂-),2.69(1H,t,-OH),2.75(1H,d,-OH),3.17-3.21 (1H,m,-OCH ₂CH<),3.31-3.37(1H,m,-OCH ₂CH<),3.39-3.43(1H,m,-OCH₂CH<),3.54(2H,t,- CH ₂-phthalimide), 7.67-7.75 (4H, m ,-phthalimide)

(embodiment 5)

To equipped with thermometer, nitrogen inlet duct, agitator, Dean-stark pipe and the 300mL three-neck flask of condensing tube In the compound (3.87g, 14.7mmol) of pouring-in (25), 4-hydroxy benzaldehyde (1.20g, 9.83mmol), pyridine to toluene Sulfonate (247mg, 0.983mmol) and toluene (180g), carry out reacting 4 hours, simultaneously by removing with toluene azeotropic distillation Water byproduct.Being added thereto to triethylamine (199mg, 1.97mmol) then stir a period of time, solvent is removed in decompression distillation.Will Residue is dissolved in chloroform, and solution cleans with 20 weight % sodium chloride solutions and ion exchange water successively, and is used by organic layer Anhydrous sodium sulfate is dried.After filtration, decompression distillation removes solvent, to obtain the compound of formula (26).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.41-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),3.57-4.26(5H,m,-OCH ₂CH<,-CH ₂-phthalyl is sub- Amine), 5.71 (0.6H, s, > CH-),5.82(0.4H,s,>CH-), 6.79-6.82 (2H, m, aromatic ring H), 7.31-7.35 (2H, m, Aromatic ring H), 7.70-7.86 (4H, m ,-phthalimide)

(embodiment 6)

To equipped with the 300mL four-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube is injected anhydrous methanol (12.8g, 0.400mol), dehydrated toluene (150g) and metallic sodium (0.3g, 13mmol), blasting the same of nitrogen in mixture Time be stirred at room temperature mixture until metallic sodium dissolve.Solution is injected in 5L autoclave, and using nitrogen exchange system Behind inside, temperature is increased to 100 DEG C.Under 1MPa pressure below, at 100 to 130 DEG C add ethylene oxide (1, 987g, 45mol) after, then sustained response 2 hours.After under reduced pressure removing unreacted ethylene oxide atmosphere, by mixture It is cooled to 60 DEG C and with 85% phosphoric acid solution, pH is adjusted to 7.5, thus obtaining the compound of formula (27).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

2.68(1H,t,OH),3.38(3H,s,CH ₃O-),3.49-3.85(450H,m,-(OCH ₂CH ₂)_n-)

Gpc analysis；Number average molecular weight (Mn): 5119, weight average molecular weight (Mw): 5226, polydispersity (Mw/ Mn): 1.021

CH₃-(OCH₂CH₂)_n-OH (27)

N=about 113

(embodiment 7)

To equipped with thermometer, nitrogen inlet duct, agitator, Dean-stark pipe and the 500mL three-neck flask of condensing tube In the compound (100g, 20.0mmol) of pouring-in (27) and toluene (250g), and by removing water with toluene azeotropic distillation. After being cooled to 40 DEG C, inject triethylamine (3.24g, 32.0mmol), be added dropwise in Dropping funnel the first of preparation wherein Sulfonic acid chloride (2.75g, 24.0mmol).After being added dropwise over, carry out reacting 3 hours at 40 DEG C.It is added thereto to ethanol (1.11g, 24.0mmol) also stirs the mixture for a period of time, filters, and dilutes by ethyl acetate (200g).By adding Hexane (500g) crystallizes, after filtration, by dissolution of crystals in ethyl acetate (500g).Again enter by adding hexane (500g) Row crystallization, after filtration, is dried under reduced pressure crystal, to obtain the compound of formula (28).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

3.08(3H,s,-OSO₂CH ₃),3.38(3H,s,CH ₃O-),3.52-3.85(448H,m,-(OCH ₂CH ₂)_n- OCH ₂-),4.37-4.39(2H,m,-CH ₂OSO₂CH₃)

Gpc analysis；Number average molecular weight (Mn): 5197, weight average molecular weight (Mw): 5306, polydispersity (Mw/ Mn): 1.021

N=about 113

(embodiment 8)

To equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (28) Compound (5.00g, 1.00mmol), the compound (551mg, 1.50mmol) of formula (26), potassium carbonate (691mg, 5.00mmol) With acetonitrile (25g), carry out reacting 4 hours at 80 DEG C.After solvent is removed in decompression distillation, residue is dissolved in ethyl acetate , and filtering solution (100g).Crystallize by adding hexane (100g), after filtration, be dried under reduced pressure crystal, to obtain formula (29) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),3.38(3H,s,CH ₃O-),3.52-4.25(455H,m,- (OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂-phthalimide), 5.72 (0.6H, s, > CH-),5.84(0.4H,s,>CH-), 6.89-6.91 (2H, m, aromatic ring H), 7.35-7.39 (2H, m, aromatic ring H), 7.70-7.86 (4H, m ,-phthalimide)

Gpc analysis；Number average molecular weight (Mn): 5462, weight average molecular weight (Mw): 5582, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 9)

To equipped with pouring-in in the 50mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (29) Compound (2.00g, 0.400mmol), methanol (7g) and ethylenediamine monohydrate (0.781g, 10.0mmol), carried out at 40 DEG C React 4 hours.With the sodium chloride solution dilution mixture thing of 20 weight %, extract with dichloromethane, and under reduced pressure distillation is gone Except solvent.Residue is dissolved in ethyl acetate (50g), is dried with anhydrous sodium sulfate, filter, and by adding hexane (50g) crystallization.After filtration, it is dried under reduced pressure crystal, to obtain the compound of formula (30).

¹H-NMR(CD₃OD, internal standard substance TMS)；δ (ppm):

1.43-1.79(6H,m,>CHCH ₂CH ₂CH ₂-),2.77(2H,t,-CH ₂-NH₂),3.36(3H,s,CH ₃O-), 3.50-4.29(453H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH<),5.70(0.6H,s,>CH-),5.81(0.4H,s,>CH-), 6.93-6.98 (2H, m, aromatic ring H), 7.33-7.41 (2H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5332, weight average molecular weight (Mw): 5454, polydispersity (Mw/ Mn): 1.023

N=about 113

(embodiment 10)

To equipped with pouring-in in the 50mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (30) Compound (0.20g, 0.040mmol) and acetonitrile (10g), be added thereto to N-succinimido-3-dimaleoyl imino third Acid esters (32mg, 0.048mmol), carries out reacting 3 hours at 25 DEG C.After filtration, solvent is removed in decompression distillation.Residue is dissolved In ethyl acetate (25g), and crystallize by adding hexane (25g).After filtration, it is dried under reduced pressure crystal, to obtain formula (31) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),2.44(2H,t,-CH ₂CH₂-maleimide), 3.27-3.37 (2H,m,-CH ₂NHCO-),3.38(3H,s,CH ₃O-),3.47-4.25(455H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH<,- CH₂CH ₂-maleimide), 5.72 (0.6H, s, > CH-),5.84(0.4H,s,>CH-),6.15(1H,brs,-NHCO-), 6.70 (2H, s ,-maleimides), 6.89-6.91 (2H, m, aromatic ring H), 7.35-7.39 (2H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5484, weight average molecular weight (Mw): 5610, polydispersity (Mw/ Mn): 1.023

N=about 113

(embodiment 11)

Use 3-fluoro-4-hydroxy benzaldehyde, obtain the compound of formula (32) with the method identical with embodiment 1 to 8.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),3.38(3H,s,CH ₃O-),3.52-4.23(455H,m,- (OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂-phthalimide), 5.70 (0.6H, s, > CH-),5.82(0.4H,s,>CH-), 6.95-7.21 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-phthalimide)

Gpc analysis；Number average molecular weight (Mn): 5485, weight average molecular weight (Mw): 5606, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 12)

Use 2-bromo-5-hydroxy benzaldehyde, obtain the compound of formula (33) with the method identical with embodiment 1 to 8.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

Gpc analysis；Number average molecular weight (Mn): 5548, weight average molecular weight (Mw): 5670, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 13)

With the compound of the method synthesis type (34) similar to embodiment 1 to 4, and use 3-fluoro-4-hydroxy benzaldehyde, The compound of formula (35) is obtained with the method identical with embodiment 5 to 8.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.89(2H,m,-CH ₂CH₂-phthalimide), 3.19 (1H, m ,-OCH₂CH<),3.38(3H,s, CH ₃O-),3.52-4.41(456H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂CH₂CH ₂-phthalimide), 5.34 (0.8H,s,>CH-),5.42(0.2H,s,>CH-), 6.95-7.25 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-adjacent benzene two Carboximide)

Gpc analysis；Number average molecular weight (Mn): 5498, weight average molecular weight (Mw): 5619, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 14)

The compound of use formula (34) and 2-bromo-5-hydroxy benzaldehyde, obtain formula with the method identical with embodiment 5 to 8 (36) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.89(2H,m,-CH ₂CH₂-phthalimide), 3.19 (1H, m ,-OCH₂CH<),3.38(3H,s, CH ₃O-),3.52-4.41(456H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂CH₂CH ₂-phthalimide), 5.61 (0.8H,s,>CH-),5.68(0.2H,s,>CH-), 6.78-7.40 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-adjacent benzene two Carboximide)

Gpc analysis；Number average molecular weight (Mn): 5564, weight average molecular weight (Mw): 5686, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 15)

N=about 113

By the compound of the formula (37) that use hydrochloric acid removal synthesizes according to the method described in JP-A-2010-248504 The tert-butyl group, it is thus achieved that the compound of formula (38).

¹H-NMR(D₂O, internal standard substance TMS)；δ (ppm):

3.14(2H,t,NH₂CH ₂-),3.40-4.00(452H,m,-(OCH ₂CH ₂)_n-OCH ₂-)

NH₂(CH₂)₂-(OCH₂CH₂)_n-OH

(38)

N=about 113

(embodiment 16)

By making the compound of formula (38) and 5-nitrine valeric anhydride react the compound of acquisition formula (39).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.60-1.74(4H,m,-CH₂CH ₂CH ₂CH₂N₃),2.18(2H,t,-CH ₂CH₂CH₂CH₂N₃),3.29(2H,t,- CH₂CH₂CH₂CH ₂N₃),3.40-3.85(454H,m,-(OCH ₂CH ₂)_n-OCH ₂-,-CONHCH ₂-),6.30(1H,brs,- CONH-)

N=about 113

(embodiment 17)

With method similar to Example 7, by the presence of triethyl amine, make compound and the mesyl chloride of formula (39) Toluene reacts, it is thus achieved that the compound of formula (40).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.60-1.74(4H,m,-CH₂CH ₂CH ₂CH₂N₃),2.18(2H,t,-CH ₂CH₂CH₂CH₂N₃),3.08(3H,s,- OSO₂CH ₃),3.29(2H,t,-CH₂CH₂CH₂CH ₂N₃),3.40-3.85(452H,m,-(OCH ₂CH ₂)_n-OCH ₂-,- CONHCH ₂-),4.37-4.39(2H,m,-CH ₂OSO₂CH₃),6.30(1H,brs,-CH₂CONH-)

N=about 113

(embodiment 18)

Use 3-fluoro-4-hydroxy benzaldehyde and the compound of formula (40), obtain with the method identical with embodiment 1 to 5 and 8 The compound of formula (41).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(10H,m,>CHCH ₂CH ₂CH ₂-,-CH₂CH ₂CH ₂CH₂N₃),2.18(2H,t,- CH ₂CH₂CH₂CH₂N₃),3.28-4.23(461H,m,-(OCH ₂CH ₂)_n-OCH ₂-,-CH₂CH₂CH₂CH ₂N₃,-CH₂CONHCH ₂-,- OCH ₂CH<,-CH ₂-phthalimide), 5.70 (0.6H, s, > CH-),5.82(0.4H,s,>CH-),6.30(1H,brs,- CH₂CONH-), 6.95-7.21 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-phthalimide)

N=about 113

(embodiment 19)

By the way of the same as in Example 9, deprotect phthalimide-based from the compound of formula (41), subsequently with Iodo acetic acid anhydride reactant, it is thus achieved that the compound of formula (42).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(10H,m,>CHCH ₂CH ₂CH ₂-,-CH₂CH ₂CH ₂CH₂N₃),2.18(2H,t,- CH ₂CH₂CH₂CH₂N₃),3.28-4.23(463H,m,-(OCH ₂CH ₂)_n-OCH ₂-,-CH₂CH₂CH₂CH ₂N₃,-CH₂CONHCH ₂-, ICH₂CONHCH ₂-,ICH ₂CONHCH₂-,-OCH ₂CH<),5.70(0.6H,s,>CH-),5.82(0.4H,s,>CH-),6.30 (1H,brs,-CH₂CONH-),6.96(1H,brs,ICH₂CONHCH₂-), 6.95-7.21 (3H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5679, weight average molecular weight (Mw): 5815, polydispersity (Mw/ Mn): 1.024

N=about 113

(embodiment 20)

N=about 113

With method same as in Example 7, make the formula (43) according to the method synthesis described in JP-A-2004-197077 Compound react with mesyl chloride, it is thus achieved that the compound of formula (44).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

3.08(3H,s,-OSO₂CH ₃),3.38(6H,s,CH ₃O-),3.40-4.00(903H,m,-(OCH ₂CH ₂)_n- OCH ₂-,-(OCH ₂CH ₂)_n-OCH<),4.26-4.42(2H,m,-CH ₂OSO₂CH₃)

N=about 113

(embodiment 21)

Use 3-fluoro-4-hydroxy benzaldehyde and the compound of formula (44), obtain with the method identical with embodiment 1 to 5 and 8 The compound of formula (45).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),3.38(6H,s,CH ₃O-),3.40-4.23(910H,m,- (OCH ₂CH ₂)_n-OCH ₂-,-(OCH ₂CH ₂)_n-OCH<,-OCH ₂CH<,-CH ₂-phthalimide), 5.70 (0.6H, s, > CH-),5.82(0.4H,s,>CH-), 6.95-7.21 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-phthalimide)

Gpc analysis；Number average molecular weight (Mn): 9761, weight average molecular weight (Mw): 9986, polydispersity (Mw/ Mn): 1.023

N=about 113

(embodiment 22)

N=about 113

In the presence of triethylamine and 4-dimethylaminopyridine, make according to the method described in JP-A-2004-197077 The compound of the formula (46) of synthesis and acetic anhydride, it is thus achieved that the compound of formula (47).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

2.08(6H,s,CH ₃CO-),3.40-4.00(901H,m,-(OCH ₂CH ₂)_n-OCH ₂-,-(OCH ₂CH ₂)_n-OCH<,- CH ₂OCH₂Ph),4.22(4H,t,CH₃CO₂CH ₂-),4.54(2H,s,-CH₂OCH ₂Ph),7.27-7.38(5H,m,- CH₂OCH₂ Ph)

N=about 113

(embodiment 23)

From the compound of formula (47), remove benzyl according to the method described in JP-A-2004-197077, subsequently with The similar method of embodiment 7 makes it react with mesyl chloride, it is thus achieved that the compound of formula (48).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

2.08(6H,s,CH ₃CO-),3.08(3H,s,-OSO₂CH ₃),3.40-4.00(899H,m,-(OCH ₂CH ₂)_n- OCH ₂-,-(OCH ₂CH ₂)_n-OCH<),4.22(4H,t,CH₃CO₂CH ₂-),4.26-4.42(2H,m,-CH ₂OSO₂CH₃)

N=about 113

(embodiment 24)

Use 3-fluoro-4-hydroxy benzaldehyde and the compound of formula (48), obtain with the method identical with embodiment 1 to 5 and 8 The compound of formula (49).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),2.08(6H,s,CH ₃CO-),3.40-4.23(910H,m,- (OCH ₂CH ₂)_n-OCH ₂-,-(OCH ₂CH ₂)_n-OCH<,-OCH ₂CH<,-CH ₂-phthalimide, CH₃CO₂CH ₂-),5.70 (0.6H,s,>CH-),5.82(0.4H,s,>CH-), 6.95-7.21 (3H, m, aromatic ring H), 7.70-7.86 (4H, m ,-adjacent benzene two Carboximide)

N=about 113

(embodiment 25)

By using ethylenediamine monohydrate deprotect phthalimide-based from the compound of formula (49) and use hydrogen Aqueous solution of sodium oxide removes acetyl group, makes itself and N-succinimido-3-Malaysia subsequently in the way of same as in Example 10 Imide propionic ester reacts, it is thus achieved that the compound of formula (50).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),2.44(2H,t,-CH ₂CH₂-maleimide), 3.27-3.37 (2H,m,-CH ₂NHCO-),3.40-4.23(910H,m,-(OCH ₂CH ₂)_n-OCH ₂-,-(OCH ₂CH ₂)_n-OCH<,-OCH ₂CH<,- CH₂CH ₂-maleimide), 5.70 (0.6H, s, > CH-),5.82(0.4H,s,>CH-),6.15(1H,brs,-NHCO-), 6.70 (2H, s ,-maleimides), 6.95-7.21 (3H, m, aromatic ring H)

N=about 113

(embodiment 26)

In the presence of triethyl amine, make the compound of formula (50) and N, N'-bis-succinimidyl carbonate at dichloromethane Alkane reacts, it is thus achieved that the compound of formula (51).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),2.44(2H,t,-CH ₂CH₂-maleimide), 2.84 (8H, s ,- Butanimide), 3.27-3.37 (2H, m ,-CH ₂NHCO-),3.40-4.23(906H,m,-(OCH ₂CH ₂)_n-OCH ₂-,- (OCH ₂CH ₂)_n-OCH<,-OCH ₂CH<,-CH₂CH ₂-maleimide), 4.44-4.48 (4H, m ,-CH ₂O-COO-succinyl is sub- Amine), 5.70 (0.6H, s, > CH-),5.82(0.4H,s,>CH-),6.15(1H,brs,-NHCO-), 6.70 (2H, s ,-maleoyl Imines), 6.95-7.21 (3H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 9955, weight average molecular weight (Mw): 10204, polydispersity (Mw/ Mn): 1.025

N=about 113

(embodiment 27)

N=about 113

With method same as in Example 7, make formula (52) by ethylene oxide polymerization being synthesized to tetramethylolmethane Compound reacts with mesyl chloride, it is thus achieved that the compound of formula (53).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

3.08(12H,s,-OSO₂CH ₃),3.47-3.85(1800H,m,-(OCH ₂CH ₂)_n-OCH ₂-),4.37-4.39(8H, m,-CH ₂OSO₂CH₃)

N=about 113

(embodiment 27)

Use 3-fluoro-4-hydroxy benzaldehyde and the compound of formula (53), obtain with the method identical with embodiment 1 to 5 and 8 The compound of formula (54).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.38-1.80(24H,m,>CHCH ₂CH ₂CH ₂-),3.52-4.23(1828H,m,-(OCH ₂CH ₂)_n-OCH ₂-,- OCH ₂CH<,-CH ₂-phthalimide), 5.70 (2.4H, s, > CH-),5.82(1.6H,s,>CH-),6.95-7.21 (12H, m, aromatic ring H), 7.70-7.86 (16H, m ,-phthalimide)

Gpc analysis；Number average molecular weight (Mn): 19645, weight average molecular weight (Mw): 20136, polydispersity (Mw/Mn): 1.025

N=about 113

(embodiment 28)

Each compound (20mg) of formula (29), formula (32), formula (33), formula (35) and formula (36) is dissolved separately in pD In the HEPES deuterated water buffer agent (1mL) of the MES deuterated water buffer agent (1mL) and pD 7.4 of 5.5 so that it is be statically placed in 37 DEG C In water bath with thermostatic control.Fig. 1 and Fig. 2 is shown respectively the measurement result of percent hydrolysis when pD 5.5 and pD 7.4.

As it is shown in figure 1, the compound of formula (29), formula (32), formula (33), formula (35) and formula (36) is at pD is 5.5,37 DEG C Percent hydrolysis half-life (t_1/2) be respectively 2 hours, 12 hours, 30 days, 24 hours and 6 months.It addition, as in figure 2 it is shown, at pD At 7.4 and 37 DEG C, the percent hydrolysis half-life (t of the compound of formula (29) and formula (32)_1/2) be respectively 65 hours and 18 days, for The compound of formula (35) observed the hydrolysis of about 17% when 18 days, and for formula (33) and formula (36) compound even Hydrolysis is not the most observed after 18 days.

(embodiment 29)

To equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (26) Compound (1.10g, 3.00mmol), methanol (53g) and ethylenediamine monohydrate (5.86g, 75.0mmol), carry out anti-at 40 DEG C Answer 4 hours.Mixture is cooled to room temperature, dilutes with the sodium-chloride water solution of 10 weight %, and extract with dichloromethane.With The sodium chloride solution of 10 weight % cleans organic layer, and is dried with anhydrous sodium sulfate.After filtration, solvent is removed in decompression distillation, To obtain the compound of formula (56).

¹H-NMR(CD₃OD, internal standard substance TMS)；δ (ppm):

1.44-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),2.77(2H,t,-CH ₂-NH₂),3.55-4.31(3H,m,- OCH₂CH<),5.70(0.6H,s,>CH-),5.81(0.4H,s,>CH-), 6.89-6.94 (2H, m, aromatic ring H), 7.29-7.37 (2H, m, aromatic ring H)

(embodiment 30)

To the compound equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct and agitator (56) (593mg, 2.50mmol) and anhydrous methanol (20g), and be added dropwise over by by Trifluoroacetic Acid Ethyl Ester (426mg, Mixture is stirred while 3.00mmol) being dissolved in the solution that anhydrous methanol (20g) obtains.After being added dropwise over, 25 DEG C carry out reacting 2 hours.Solvent is removed in decompression distillation, and is dried under reduced pressure residue, to obtain the chemical combination of formula (57) Thing.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.44-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),3.57-4.26(5H,m,-OCH ₂CH<,-CH ₂-NHCOCF₃), 5.71(0.6H,s,>CH-),5.82(0.4H,s,>CH-), 6.79-6.82 (2H, m, aromatic ring H), 7.31-7.35 (3H, m, aromatic ring H,-NHCOCF₃)

(embodiment 31)

N=about 113

With method same as in Example 7, make the formula (58) according to the method synthesis described in JP-A-2010-138388 Compound react with mesyl chloride, subsequently use hydrochloric acid remove the tert-butyl group, it is thus achieved that the compound of formula (59).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

2.68(1H,t,-OH),3.08(3H,s,-OSO₂CH ₃),3.52-3.85(448H,m,-(OCH ₂CH ₂)_n-OCH ₂-), 4.37-4.39(2H,m,-CH ₂OSO₂CH₃)

Gpc analysis；Number average molecular weight (Mn): 5195, weight average molecular weight (Mw): 5309, polydispersity (Mw/ Mn): 1.022

(embodiment 32)

N=about 113

To equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (59) Compound (5.00g, 1.00mmol), the compound (500mg, 1.50mmol) of formula (57), potassium carbonate (691mg, 5.00mmol) With acetonitrile (25g), carry out reacting 4 hours at 80 DEG C.After solvent is removed in decompression distillation, residue is dissolved in ethyl acetate , and filtering solution (100g).Crystallize by adding hexane (100g), after filtration, be dried under reduced pressure crystal, to obtain formula (60) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),2.68(1H,t,-OH),3.52-4.25(455H,m,- (OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂-NHCOCF₃),5.72(0.6H,s,>CH-),5.84(0.4H,s,>CH-),6.89- 6.91 (2H, m, aromatic ring H), 7.31-7.39 (3H, m, aromatic ring H ,-NHCOCF₃)

Gpc analysis；Number average molecular weight (Mn): 5432, weight average molecular weight (Mw): 5552, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 33)

To the compound equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct and agitator (60) (1.00g, 0.200mmol) and dichloromethane (5g), be added thereto to glutaric anhydride (34.2mg, 0.300mmol), triethylamine (30.4mg, 0.300mmol) and 4-dimethylaminopyridine (1.2mg, 0.015mmol), carry out reacting 6 hours at 25 DEG C.Cross After filter, solvent is removed in decompression distillation.Residue is dissolved in methanol (2.5g), is added thereto to 1M wet chemical (5g), And carry out reacting 3 hours at 25 DEG C.With the sodium-chloride water solution dilution mixture thing of 20 weight %, extract with dichloromethane, and And under reduced pressure solvent is removed in distillation.Residue is dissolved in ethyl acetate (50g), is dried with anhydrous sodium sulfate, filter, and Crystallize by adding hexane (50g).After filtration, it is dried under reduced pressure crystal, to obtain the compound of formula (61).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),1.97(2H,quin,-CH₂CH ₂CH₂COOH),2.38-2.46 (4H,m,-CH ₂CH₂CH ₂COOH),2.71(2H,t,-CH ₂-NH₂),3.52-4.27(455H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH <,-CH _bO-COCH₂-),5.72(0.6H,s,>CH-),5.84(0.4H,s,>CH-), 6.89-6.91 (2H, m, aromatic ring H), 7.35-7.39 (2H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5449, weight average molecular weight (Mw): 5569, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 34)

To equipped with thermometer, nitrogen inlet duct, agitator, Dean-stark pipe and the 300mL three-neck flask of condensing tube Middle injection 1,2,6-hexanetriol (2.01g, 15.0mmol), 4-hydroxy benzaldehyde (1.22g, 10.0mmol), p-methyl benzenesulfonic acid one Hydrate (19.0mg, 0.100mmol) and toluene (183g), carry out reacting 4 hours, simultaneously by removing with toluene azeotropic distillation Water byproduct.It is added thereto to triethylamine (20.2mg, 0.200mmol) then stir a period of time, with the chlorination of 10 weight % Sodium solution washed mixture, and it is dried organic layer with anhydrous sodium sulfate.After filtration, decompression distillation removes solvent, to obtain formula (62) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.42-1.80(6H,m,>CHCH ₂CH ₂CH ₂-),3.57-4.26(5H,m,-OCH ₂CH<,-CH ₂-OH),5.71 (0.6H,s,>CH-),5.82(0.4H,s,>CH-), 6.79-6.82 (2H, m, aromatic ring H), 7.31-7.35 (2H, m, aromatic ring H)

(embodiment 35)

To equipped with pouring-in in the 100mL three-neck flask of thermometer, nitrogen inlet duct, agitator and condensing tube (28) Compound (5.00g, 1.00mmol), the compound (357mg, 1.50mmol) of formula (62), potassium carbonate (691mg, 5.00mmol) With acetonitrile (25g), carry out reacting 4 hours at 80 DEG C.After solvent is removed in decompression distillation, residue is dissolved in ethyl acetate , and filtering solution (100g).Crystallize by adding hexane (100g), after filtration, be dried under reduced pressure crystal, to obtain formula (63) compound.

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.40-1.81(6H,m,>CHCH ₂CH ₂CH ₂-),3.38(3H,s,CH ₃O-),3.52-4.25(455H,m,- (OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂-OH),5.72(0.6H,s,>CH-),5.84(0.4H,s,>CH-),6.89-6.91(2H, M, aromatic ring H), 7.35-7.39 (2H, m, aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5332, weight average molecular weight (Mw): 5449, polydispersity (Mw/ Mn): 1.022

N=about 113

(embodiment 36)

In the presence of triethyl amine, make the compound of formula (63) and N, N'-bis-succinimidyl carbonate at dichloromethane Alkane reacts, it is thus achieved that the compound of formula (64).

¹H-NMR(CDCl₃, internal standard substance TMS)；δ (ppm):

1.45-1.87(6H,m,>CHCH ₂CH ₂CH ₂-), 2.84 (4H, two unimodal (two singlets) ,-succinyl Asias Amine), 3.38 (3H, s, CH _bO-),3.52-4.38(455H,m,-(OCH ₂CH ₂)_n-,-OCH ₂CH<,-CH ₂O-COO-succinyl is sub- Amine), 5.72 (0.6H, s, > CH-),5.84(0.4H,s,>CH-), 6.89-6.91 (2H, m, aromatic ring H), 7.35-7.39 (2H, m, Aromatic ring H)

Gpc analysis；Number average molecular weight (Mn): 5470, weight average molecular weight (Mw): 5590, polydispersity (Mw/ Mn): 1.022

N=about 113

Although the most in detail and with reference to detailed description of the invention, invention has been described, but for those skilled in the art For, it is clear that various changes and modifications can be made wherein when without departing substantially from the spirit and scope of the present invention.

Japanese patent application No. 2014-72356 that the present invention submitted to based on March 31st, 2014 and JIUYUE in 2014 22 days Japanese patent application No. 2014-193039 submitted to, entire contents is incorporated herein by.And, cited herein All lists of references are integrally incorporated herein with it.

Claims

1. a hydrophilic polymer derivant, this hydrophilic polymer derivant has ring-type benzylidene acetal linker Group, is represented by following formula (1):

Wherein, R¹And R⁶It is hydrogen atom or alkyl independently of one another；R²、R³、R⁴And R⁵Be independently of one another electrophilic or give electronics Substituent group or hydrogen atom；X¹It it is chemical reactivity functional group；P is hydrophilic polymer；S is 1 or 2, and t is 0 or 1, and s+t is 1 or 2；W is the integer of 1 to 8；And Z¹And Z²It it is the divalent spacer thing being each independently selected.

Hydrophilic polymer derivant the most according to claim 1, wherein, s is 1 and t to be 0, R²And R⁵Independently of one another It is hydrogen atom, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-0.30≤Σ σ≤1.05.

Hydrophilic polymer derivant the most according to claim 1, wherein, s is 1 and t to be 0, R²And R⁵In at least one Individual is described substituent group, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-1.71≤Σ σ≤0.88.

Hydrophilic polymer derivant the most according to claim 1, wherein, s is 1 and t to be 1, or s is 2 and t to be 0, R²And R⁵It is hydrogen atom independently of one another, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet-0.19≤ Σσ≤0.57。

Hydrophilic polymer derivant the most according to claim 1, wherein, s is 1 and t to be 1, or s is 2 and t to be 0, R²And R⁵In at least one be described substituent group, and R³、R⁴And P-Z¹Substituent constant (σ) summation (Σ σ) meet- 0.98≤Σσ≤0.48。

6. according to the hydrophilic polymer derivant described in any one of claim 1 to 5, wherein, X¹Select free active ester groups, work Property carbonate group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfuryl, acrylic acid Base, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl, vinyl, amino, oxygen ammonia The group that base, hydrazide group and azido are formed.

7. according to the hydrophilic polymer derivant described in any one of claim 1 to 6, wherein, X¹Select free style (a), formula (b), Formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and formula (n) institute group The group become:

Wherein, R⁷It is hydrogen atom or sulfo group；R⁸And R¹¹It is hydrogen atom or the alkyl with 1 to 5 carbon atom independently of one another；R⁹ Being the alkyl with 1 to 10 carbon atom, this alkyl can comprise halogen atom；And R¹⁰Be selected from chlorine atom, bromine atoms and The halogen atom of atomic iodine.

8. according to the hydrophilic polymer derivant described in any one of claim 1 to 7, wherein, Z¹And Z²It is ether independently of one another Key, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the alkylidene of group, list Key or alkylidene, and at Z¹And Z²At least one be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, parahelium Base or in the case of comprising these keys arbitrary and the alkylidene of group and being connected to multiple constitutional repeating unit, this structure list The quantity of unit is less than 2.

9. according to the hydrophilic polymer derivant described in any one of claim 1 to 8, wherein, P be end have alkyl or The linear type Polyethylene Glycol of chemical reactivity functional group.

Hydrophilic polymer derivant the most according to claim 9, wherein, w be 1 and P by formula (2) represent:

Y-(OCH₂CH₂)_n- (2)

Wherein, Y is the alkyl with 1 to 24 carbon atom；And n is the integer of 3 to 2000.

11. hydrophilic polymer derivants according to claim 9, wherein, w be 1 and P by formula (3) represent:

X²-Z³-(OCH₂CH₂)_n- (3)

Wherein, X²It is different from X¹Chemical reactivity functional group；Z³It it is divalent spacer thing；And n is the integer of 3 to 2000.

12. according to the hydrophilic polymer derivant described in any one of claim 1 to 8, and wherein, P is to have difference at end In X¹Alkyl or the branched chain type Polyethylene Glycol of chemical reactivity functional group.

13. hydrophilic polymer derivants according to claim 12, wherein, w be 1 and P by formula (4) represent:

Wherein, Y is the alkyl with 1 to 24 carbon atom；N is the integer of 3 to 1000；And v is 0 or 2.

14. hydrophilic polymer derivants according to claim 12, wherein, w be 1 and P by formula (5) represent:

Wherein, X²It is different from X¹Chemical reactivity functional group；Z³It it is divalent spacer thing；N is the integer of 3 to 1000；And v It is 0 or 2.

15. hydrophilic polymer derivants according to claim 12, wherein, w is that v+2 and P is represented by formula (6):

16. according to the hydrophilic polymer derivant according to any one of claim 11,14 and 15, wherein, X²Choosing freely activity Ester group, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, dimaleoyl imino, vinyl sulfone Base, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, pi-allyl, vinyl, The group that amino, oxygen amino, hydrazide group and azido are formed.

17. according to the hydrophilic polymer derivant according to any one of claim 11,14 and 15, wherein, X²Select free style (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula (k), formula (l), formula (m) and The group that formula (n) is formed:

18. according to the hydrophilic polymer derivant according to any one of claim 11,14 and 15, wherein, Z³It is ehter bond, ester Key, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group, comprise these keys arbitrary and the alkylidene of group, singly-bound or Alkylidene, and at Z³Be ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group or comprise arbitrary this A little keys and the alkylidene of group and in the case of being connected to multiple constitutional repeating unit, the quantity of this construction unit is less than 2.

19. according to the hydrophilic polymer derivant described in any one of claim 1 to 8, wherein, P be have 2 to 8 end The Polyethylene Glycol of number, the whole end of Polyethylene Glycol constituting P is each attached to Z¹, and w is equal to the end number of Polyethylene Glycol.

20. hydrophilic polymer derivants according to claim 19, wherein, P select free style (r), formula (s), formula (t), The group that formula (u) and formula (v) are formed:

Wherein, n is the integer of 3 to 2000, and when P is represented by formula (r) w be 2, when P is represented by formula (s) w be 3, P by Formula (t) represent time w be 4, when P is represented by formula (u) w be 4 and when P is represented by formula (v) w be 8.

21. 1 kinds of ring-type benzylidene acetal linking group compounds, are represented by following formula (55):

Wherein, R¹And R⁶It is hydrogen atom or alkyl independently of one another；R²、R³、R⁴And R⁵Be independently of one another electrophilic or give electronics Substituent group or hydrogen atom；X³And X⁴Can be identical or different, it is chemical reactivity functional group independently of one another；S is 1 or 2, and t is 0 Or 1, and s+t is 1 or 2；And Z¹And Z²It it is the divalent spacer thing being each independently selected.

22. ring-type benzylidene acetal linking group compounds according to claim 21, wherein, s is 1 and t to be 0, R² And R⁵It is hydrogen atom independently of one another, and R³、R⁴And X³-Z¹Substituent constant (σ) summation (Σ σ) meet-0.30≤Σ σ ≤1.05。

23. ring-type benzylidene acetal linking group compounds according to claim 21, wherein, s is 1 and t to be 0, R² And R⁵In at least one be described substituent group, and R³、R⁴And X³-Z¹Substituent constant (σ) summation (Σ σ) meet- 1.71≤Σσ≤0.88。

24. ring-type benzylidene acetal linking group compounds according to claim 21, wherein, s is 1 and t to be 1, Or s is 2 and t to be 0, R²And R⁵It is hydrogen atom independently of one another, and R³、R⁴And X³-Z¹The summation of substituent constant (σ) (Σ σ) meets-0.19≤Σ σ≤0.57.

25. ring-type benzylidene acetal linking group compounds according to claim 21, wherein, s is 1 and t to be 1, Or s is 2 and t to be 0, R²And R⁵In at least one be described substituent group, and R³、R⁴And X³-Z¹Substituent constant (σ) Summation (Σ σ) meet-0.98≤Σ σ≤0.48.

26. according to the ring-type benzylidene acetal linking group compound described in any one of claim 21 to 25, wherein, X³With X⁴It each is selected from by active ester groups, active carbonic acid ester group, aldehyde radical, NCO, isothiocyanate group, epoxy radicals, maleoyl Imido grpup, vinyl sulfuryl, acrylic, sulfonyloxy, carboxyl, sulfydryl, dithiopyridines base, alpha-halogen acetyl group, alkynyl, The group that pi-allyl, vinyl, amino, oxygen amino, hydrazide group, azido and hydroxyl are formed.

27. according to the ring-type benzylidene acetal linking group compound described in any one of claim 21 to 26, wherein, X³With X⁴It each is selected from by formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h), formula (i), formula (j), formula K group that (), formula (l), formula (m), formula (n) and formula (o) are formed:

28. according to the ring-type benzylidene acetal linking group compound described in any one of claim 21 to 27, wherein, Z¹With Z²It is ehter bond, ester bond, carbonic acid ester bond, amino-formate bond, amido link, secondary amino group independently of one another, comprises these keys arbitrary With alkylidene, singly-bound or the alkylidene of group, and at Z¹And Z²At least one be ehter bond, ester bond, carbonic acid ester bond, amino first Acid esters key, amido link, secondary amino group or comprise these keys arbitrary and the alkylidene of group and be connected to multiple repetitive structure list In the case of unit, the quantity of this construction unit is less than 2.

29. according to the ring-type benzylidene acetal linking group compound described in any one of claim 21 to 28, wherein, constitutes X³And X⁴In the functional group of any one comprise protectiveness group.